Evidence for Alpha7 Nicotinic Receptor Activation During the Cough Suppressing Effects Induced by Nicotine and Identification of ATA-101 as a Potential Novel Therapy for the Treatment of Chronic Cough.

Studies performed in healthy smokers have documented a diminished responsiveness to tussive challenges, and several lines of experimental evidence implicate nicotine as an antitussive component in both cigarette smoke and the vapors generated by electronic cigarettes (eCigs). We set out to identify the nicotinic receptor subtype involved in the antitussive actions of nicotine and to further evaluate the potential of nicotinic receptor-selective agonists as cough-suppressing therapeutics. We confirmed an antitussive effect of nicotine in guinea pigs. We additionally observed that the alpha-4 beta-2 (α 4 ß 2)-selective agonist Tc-6683 was without effect on evoked cough responses in guinea pigs, while the α 7-selective agonist PHA 543613 dose-dependently inhibited evoked coughing. We subsequently describe the preclinical evidence in support of ATA-101, a potent and highly selective (α 7) selective nicotinic receptor agonist, as a potential candidate for antitussive therapy in humans. ATA-101, formerly known as Tc-5619, was orally bioavailable and moderately central nervous system (CNS) penetrant and dose-dependently inhibited coughing in guinea pigs evoked by citric acid and bradykinin. Comparing the effects of airway targeted administration versus systemic dosing and the effects of repeated dosing at various times prior to tussive challenge, our data suggest that the antitussive actions of ATA-101 require continued engagement of α 7 nicotinic receptors, likely in the CNS. Collectively, the data provide the preclinical rationale for α 7 nicotinic receptor engagement as a novel therapeutic strategy for cough suppression. The data also suggest that α 7 nicotinic acetylcholine receptor (nAChR) activation by nicotine may be permissive to nicotine delivery in a way that may promote addiction. SIGNIFICANCE STATEMENT: This study documents the antitussive actions of nicotine and identifies the α7 nicotinic receptor subtype as the target for nicotine during cough suppression described in humans. We additionally present evidence suggesting that ATA-101 and other α7 nicotinic receptor-selective agonists may be promising candidates for the treatment of chronic refractory cough.

Opinion Paper: On the Diagnosis/Classification of Sexual Arousal Concerns in Women.

BACKGROUND: In the professional literature and among our professional societies, female sexual dysfunction nomenclature and diagnostic criterion sets have been the source of considerable controversy. Recently, a consensus group, supported by the International Society for Women's Sexual Health, published its recommendations for nosology and nomenclature, which included only one type of arousal dysfunction, female genital arousal disorder, in its classification system. Subjective arousal was considered an aspect of sexual desire and not part of the arousal phase. AIM: To advocate for the importance of including subjective arousal disorder in the diagnostic nomenclature in addition to the genital arousal subtype. METHODS: We reviewed how the construct of subjective arousal was included in or eliminated from the iterations of various diagnostic and statistical manuals. The Female Sexual Function Index (FSFI) was used to examine the relations among subjective arousal, genital arousal, and desire in women with and without sexual arousal concerns. MAIN OUTCOME MEASURES: Sexual arousal through a self-report Film Scale, physiologic sexual arousal through vaginal photoplethysmography in response to an erotic film, and the FSFI. RESULTS: The clinical literature and experience support differentiating subjective arousal from desire and genital arousal. Correlations between the FSFI domains representing desire and subjective arousal, although sufficient to suggest relatedness, share approximately 58% of the variance between constructs-a lower shared variance than FSFI domains representing subjective arousal and orgasm. Similarly, when looking at FSFI individual items best representative of sexual desire and subjective arousal, the large majority of the variance in subjective arousal was unexplained by desire. A third line of evidence showed no significant difference in levels of subjective arousal to erotic films between sexually functional women and women with desire problems. If desire and subjective arousal were the same construct, then one would expect to see evidence of low subjective arousal in women with low sexual desire. CLINICAL IMPLICATIONS: Optimized treatment efficacy requires differentiating mental and physical factors that contribute to female sexual dysfunction. STRENGTHS AND LIMITATIONS: Support for our conclusion is based on clinical qualitative evidence and quantitative evidence. However, the quantitative support is from only one laboratory at this time. CONCLUSION: These findings strongly support the view that female sexual arousal disorder includes a subjective arousal subtype and that subjective arousal and desire are related but not similar constructs. We advocate for the relevance of maintaining subjective arousal disorder in the diagnostic nomenclature and present several lines of evidence to support this contention. Althof SE, Meston CM, Perelman M, et al. Opinion Paper: On the Diagnosis/Classification of Sexual Arousal Concerns in Women. J Sex Med 2017;14:1365-1371.

Reexamining the Definitions of PE and DE.

Evidence-based definitions improve clinical practice and research. Nonetheless, the International Society of Sexual Medicine (ISSM) and the American Psychiatric Association's (DSM-5) definitions regarding lifelong and acquired premature ejaculation (PE) and delayed ejaculation (DE) require reexamination. Existing Intravaginal Ejaculation Latency Time (IELT) evidence, the ISSM position papers, and articles both supporting and critiquing the ISSM's definitions were reviewed. Disproportionately, the findings from those studies document that the majority of men's IELT range is approximately 4 to 10 minutes. Such robust quantitative evidence should become the basis for determining the temporal criterion when defining both PE and DE. Any bilateral deviation from that majority's ∼4- to 10-minute IELT range should meet the qualification for the temporal diagnostic criterion. However, for a man to be diagnosed with a disorder, a licensed health-care clinician (HCC) must also determine that the man suffers from "lack of control" and "distress." Diagnosis would include subtyping Lifelong or Acquired, Global or Situational, similar to the ISSM guidelines and specifying mild, moderate, or severe-similar to DSM-5 requirements. "Control" and "distress" should trump latency and convey greater weight in the diagnostic process. Loosened latency criteria could result in false positive diagnoses; however, requiring a licensed HCC to evaluate control and distress reduces that risk.

Toward a More Evidence-Based Nosology and Nomenclature for Female Sexual Dysfunctions-Part II.

INTRODUCTION: Current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definitions of sexual dysfunction do not identify all sexual problems experienced clinically by women and are not necessarily applicable for biologic or biopsychosocial management of female sexual dysfunction. A unified nomenclature system enables clinicians, researchers, and regulatory agencies to use the same language and criteria for determining clinical end points, assessing research results, and managing patients. AIM: To develop nomenclature with classification systems for female sexual desire, arousal, and orgasm disorders with definitions pertinent to clinicians and researchers from multiple specialties who contribute to the field of sexual medicine. METHODS: Key national and international opinion leaders diverse in gender, geography, and areas of expertise met for 2 days to discuss and agree to definitions of female sexual desire, arousal, and orgasm disorders and persistent genital arousal disorder. The attendees consisted of 10 psychiatrists and psychologists; 12 health care providers in specialties such as gynecology, internal medicine, and sexual medicine; three basic scientists; and one sexuality educator, representing an array of societies working within the various areas of sexual function and dysfunction. MAIN OUTCOME MEASURE: A unified set of definitions was developed and accepted for use by the International Society for the Study of Women's Sexual Health (ISSWSH) and members of other stakeholder societies participating in the consensus meeting. RESULTS: Current DSM-5 definitions, in particular elimination of desire and arousal disorders as separate diagnoses and lack of definitions of other specific disorders, were adapted to create ISSWSH consensus nomenclature for distressing sexual dysfunctions. The ISSWSH definitions include hypoactive sexual desire disorder, female genital arousal disorder, persistent genital arousal disorder, female orgasmic disorder, pleasure dissociative orgasm disorder, and female orgasmic illness syndrome. CONCLUSION: Definitions for female sexual dysfunctions that reflect current science provide useful nomenclature for current and future management of women with sexual disorders and development of new therapies.

Treatment satisfaction of men and partners following switch from on-demand phosphodiesterase type 5 inhibitor therapy to tadalafil 5 mg once daily.

INTRODUCTION: Treatment satisfaction of men receiving phosphodiesterase 5 inhibitors (PDE5) for erectile dysfunction (ED) and their partners is essential to successful long-term therapy. AIM: This study aims to assess treatment satisfaction, in men with a partial response to on-demand (PRN) PDE5 and their female partners, following tadalafil 5 mg once daily or placebo. METHODS: The study was randomized, double-blind, parallel, and placebo-controlled in men primarily with mild to moderate ED. Treatment satisfaction was assessed following a 4-week maximum dose PRN lead-in, 4-week nondrug washout, and treatment through 12 weeks. Men were ≥18 years old with ED for ≥3 months and International Index of Erectile Function Erectile Function score of ≥17 and <26 at screening and <26 following PRN lead-in. MAIN OUTCOME MEASURES: Treatment satisfaction was assessed using the Treatment Satisfaction Scale (TSS) for patients and partners. TSS domain scores range from 0 to 100, with higher values indicating greater satisfaction. Statistical comparisons were made using analysis of covariance. RESULTS: Treatment satisfaction was significantly greater with tadalafil once daily vs. placebo across all TSS domains for both patients and their partners (all P < 0.001). For patients, mean scores for the TSS domains Confidence to Complete Sexual Activity and Satisfaction with Orgasm ranged from 53.7 to 57.8 after the PRN lead-in and 26.7 to 31.9 following the nondrug washout. Following randomized treatment, scores for tadalafil and placebo were 55.4 and 32.6, respectively, for Confidence to Complete Sexual Activity and 57.5 and 37.9, respectively, for Satisfaction with Orgasm. Results were comparable for other TSS domains and between men and their partners. CONCLUSIONS: Treatment satisfaction was comparable for tadalafil 5 mg once daily and PRN PDE5 for both patients and female partners, suggesting that tadalafil once daily is a viable therapy option for men with ED who had a partial response to PRN PDE5 therapy.

Standard operating procedures for taking a sexual history.

INTRODUCTION: While there is evidence of increased professional and public awareness of sexual problems, both male and female sexual dysfunctions remain underdiagnosed and undertreated by health care professionals around the world. Health care professionals (HCPs) are typically reluctant, disinterested, or unskilled in sexual problem management and regrettably are often disinclined to inquire about sexual issues. HCPs in all countries receive variable, nonstandardized, or inadequate training in sexual history taking and its treatment. AIM: This article presents a standard operating procedure (SOP) for taking a sexual history from men or women with sexual problems or performance concerns. METHODS: Review of relevant evidence-based literature identified through a PubMed search, integrated with expert opinion. RESULTS: Guidelines for taking a sexual history are presented along with the relevant domains, opening and follow-up questions. CONCLUSIONS: The SOP presented in this article offers HCPs a brief, structured, and uniform method for obtaining a sexual history from men or women seeking health care services. Sexual history taking should be based on three basic principles, which serve as the foundation for managing sexual problems in men and women. These include the following: (i) a patient-centered approach; (ii) evidenced-based diagnostic and treatment recommendations; and (iii) use of a unified management approach for men and women. Sexual history taking should always be conducted in a culturally sensitive manner, taking account of the individual's background and lifestyle, status of the partner relationship, and the clinician's comfort and experience with the topic. Sexual inquiry should be incorporated into all new patient encounters, when possible, if only to ask one or two broad questions such as the following: "Are you sexually active? Do you have any sexual concerns or problems you would like to discuss?" Sexual history taking is a cornerstone of sexual medicine clinical practice. All patients should be provided an opportunity for frank and open discussion of sexual issues or concerns, conducted in an atmosphere of sensitivity and respect.

A pharmacokinetic assessment of an alternate titration strategy for fentanyl pectin nasal spray.

OBJECTIVE: Fentanyl pectin nasal spray (FPNS) is approved for management of breakthrough pain in cancer. It is available in 100 and 400 µg strength products which allow for doses of 100 - 800 µg (1 or 2 sprays). Existing titration strategies require a transition from the 100 µg product to the 400 µg product when increasing the dose from 200 to 400 µg. This study assessed the pharmacokinetic (PK) profile of FPNS administered as 4 sprays of 100 µg as an alternate titration strategy. METHODS: In this 3-way, crossover study, healthy subjects aged 18 - 65 years were randomized to receive each of 3 dosages of FPNS (4 × 100 µg, 2 × 100 µg, and 1 × 400 µg). PK samples were collected over 24 hours. RESULTS: Of 22 subjects randomized, 20 were included in the PK analysis. Administration of both 400 µg regimens (4 × 100 µg and 1 × 400 µg) provided greater systemic fentanyl exposure compared with the 200 µg dose (C(max): 1,748 and 1,485 pg/ml vs. 1,051 pg/ml; AUC(0-1h): 1,012 and 944 pg×h/ml vs. 665 pg×h/ml; and tmax: 0.25 hours and 0.50 hours vs. 0.25 hours); fentanyl exposure after 4 × 100 µg and 1 × 400 µg regimens was similar. Adverse events (AEs) were all mild or moderate in intensity; most common AEs were nausea (50%) and headache (23%). AE frequency was similar across treatments without reports of nasal effects. CONCLUSIONS: Given that systemic fentanyl exposure from FPNS administered as 4 × 100 µg is similar to that from FPNS as 1 × 400 µg, the 4 × 100 µg regimen provides an alternate titration strategy for patients needing more than 200 µg. This alternate strategy will facilitate a patient's ability to achieve an optimized FPNS regimen and reduce opioid wastage.

Impact of allergic rhinitis and its treatment on the pharmacokinetics of nasally administered fentanyl.

OBJECTIVES: Fentanyl pectin nasal spray (FPNS, Lazanda® in the US and PecFent® in Europe and Australia) is a novel analgesic approved for the management of breakthrough pain in cancer patients. Given that the fentanyl is nasally administered, it is important to understand whether concomitant allergic rhinitis, or its treatment with a vasoconstrictor, would affect its absorption and, potentially, its efficacy or safety. METHODS AND SUBJECTS: Subjects with a history of allergic rhinitis were screened to identify subjects who developed at least moderate rhinitis symptoms on exposure to pollen allergen (either ragweed or tree) in an environmental exposure chamber (EEC). These were entered into a randomized, three-way crossover study in which each subject received 100 µg of FPNS under three exposure conditions; Control (no rhinitis), Rhinitis (symptomatic without decongestant), Treated (symptomatic with concomitant oxymetazoline). Blood samples for fentanyl were collected over a 24-hour period. RESULTS: A total of 132 subjects was screened to identify 54 for inclusion in the study; 31 were evaluable for pharmacokinetics. Measures of fentanyl absorption (mean or median) were similar between Control and Rhinitis conditions: Cmax 453.0 vs. 467.8 pg/ml; AUCt 1,292.3 vs. 1,325.4 pg×h/ml, AUC0-∞ 1,430.6 vs. 1,387 pg×h/ml and tmax 20 vs. 17 minutes. When oxymetazoline was co-administered, overall fentanyl absorption was slightly reduced (AUC0-∞ 1,362.4 pg×h/ml); but, more clinically relevant were the delayed rate of absorption (tmax 53 minutes) and reduced Cmax (235.3 pg/ml). CONCLUSIONS: Patients treated with FPNS will be unaffected by the development of allergic rhinitis; but, if oxymetazoline is prescribed, the patient would benefit from added supervision when oxymetazoline is started and stopped.

Development of in vitro models to demonstrate the ability of PecSys®, an in situ nasal gelling technology, to reduce nasal run-off and drip.

UNLABELLED: Many of the increasing number of intranasal products available for either local or systemic action can be considered sub-optimal, most notably where nasal drip or run-off give rise to discomfort/tolerability issues or reduced/variable efficacy. PecSys, an in situ gelling technology, contains low methoxy (LM) pectin which gels due to interaction with calcium ions present in nasal fluid. PecSys is designed to spray readily, only forming a gel on contact with the mucosal surface. The present study employed two in vitro models to confirm that gelling translates into a reduced potential for drip/run-off: (i) Using an inclined TLC plate treated with a simulated nasal electrolyte solution (SNES), mean drip length [±SD, n = 10] was consistently much shorter for PecSys (1.5 ± 0.4 cm) than non-gelling control (5.8 ± 1.6 cm); (ii) When PecSys was sprayed into a human nasal cavity cast model coated with a substrate containing a physiologically relevant concentration of calcium, PecSys solution was retained at the site of initial deposition with minimal redistribution, and no evidence of run-off/drip anteriorly or down the throat. In contrast, non-gelling control was significantly more mobile and consistently redistributed with run-off towards the throat. CONCLUSION: In both models PecSys significantly reduced the potential for run-off/drip ensuring that more solution remained at the deposition site. In vivo, this enhancement of retention will provide optimum patient acceptability, modulate drug absorption and maximize the ability of drugs to be absorbed across the nasal mucosa and thus reduce variability in drug delivery.

The Subjective Sexual Arousal Scale for Men (SSASM): preliminary development and psychometric validation of a multidimensional measure of subjective male sexual arousal.

INTRODUCTION: Sexual arousal is a multifaceted process that involves both mental and physical components. No instrument has been developed and validated to assess subjective aspects of male sexual arousal. AIM: To develop and psychometrically validate a self-administered scale for assessing subjective male sexual arousal. METHODS: Using recommendations of the Food and Drug Administration (FDA) guidance on patient-reported outcome instruments, important aspects of male sexual arousal were identified via qualitative research (focus groups and interviews) of U.S. men with erectile dysfunction (ED) and healthy controls. After a preliminary questionnaire was developed by a panel of experts, a quantitative study of men with ED and controls was conducted to psychometrically validate the Subjective Sexual Arousal Scale for Men (SSASM). MAIN OUTCOME MEASURES: To develop a male sexual arousal scale and determine its factor structure, reliability, and construct validity. RESULTS: Five aspects of male sexual arousal were identified from the qualitative focus groups and cognitive interviews. Men's preferred language for describing sexual arousal and preferred response formats were incorporated into the questions. Factor analysis of data from the quantitative study of 304 men aged 21 to 70 years identified five domains with eigenvalues >1: sexual performance (six items), mental satisfaction (five items), sexual assertiveness (three items), partner communication (three items), and partner relationship (three items). The five domains had a high degree of internal consistency (Cronbach's alpha values 0.88-0.94). Test-retest reliability over a 2- to 4-week period was high-moderately high (r values 0.75-0.88) for the five domain scores. Correlations between SSASM domain scores and standardized scale scores for social desirability, general health, life satisfaction, and sexual function demonstrated the construct validity of the scale. CONCLUSIONS: Preliminary validation data suggest that the 20-item SSASM scale may be useful as a multidimensional, reliable, self-administered instrument for assessing subjective sexual arousal in men of different ages.

The controversial role of phosphodiesterase type 5 inhibitors in the treatment of premature ejaculation.

INTRODUCTION: It is controversial whether or not the most frequent male sexual dysfunctions, premature ejaculation (PE) and erectile dysfunction (ED), share pathogenetic mechanisms and treatments. METHODS: Three scientists (C.McM., J.C., and A.A.), together with the Controversy's Editor (E.A.J.), with expertise in the area of medical treatment of PE, present different perspectives on the use of phosphodiesterase type 5 inhibitors (PDE5is) in PE. The psychological point of view is discussed by an expert in sexology (M.P.). MAIN OUTCOME MEASURE: Outcome measures used are expert opinions supported by the critical review of the currently available literature. RESULTS: This Controversy examines the role of nitric oxide (NO) as a neurotransmitter involved in the central and peripheral control of ejaculation, the adherence of methodology to the contemporary consensus of ideal PE drug trial design, the impact of methodology on treatment outcomes, and the role of PDE5i drugs (sildenafil, tadalafil, and vardenafil) in the treatment of PE. CONCLUSIONS: While it is evident that PDE5is are the first choice in patients with comorbid ED and PE (where one may be secondary to the other), well-designed studies on the possible use of PDE5is in PE patients without ED are still limited. The issue will be less controversial when further evidence on the role of NO and PDE5 in the mechanism of ejaculation is available.

Standards for clinical trials in sexual dysfunction in women: research designs and outcomes assessment.

INTRODUCTION: Clinical trial design in female sexual dysfunction (FSD) is an evolving science, with some areas of controversy. AIM: To develop an evidence-based, expert consensus-report on design of FSD clinical research. METHODS: Literature review including the Food and Drug Administration (FDA) clinical trial guidelines with critique by six experts from three countries, modified after public presentation and debate. MAIN OUTCOME MEASURE: Expert opinion and recommendations were based on grading of evidence based literature, internal committee dialogue, open presentation, and debate. RESULTS: Design of clinical research for regulatory approval is driven by FDA guidelines. Diagnostic and Statistical Manual-IV definitions and consideration of comorbidity of sexual disorders may complicate patient selection and outcomes. Measures for study end points include satisfying sexual events utilizing a daily diary, sexual distress, and patient-reported outcomes measures of the construct under study. Currently, trial duration is recommended to be 6 months for efficacy trials to allow for modification of behavioral adaptations to changes in desire. Important issues include safety assessments, generalizability, having a representative study population, stratification by reproductive status, partner assessment, contextual and interpersonal factors, symptom duration and severity, management of placebo response, and drug dosing. Statistical analysis should include assessment of change from baseline to end point between study drug and placebo, determination of statistically significant change vs. clinically meaningful effects, linear mapping of all measures of the same construct, and determination of responders and remitters. CONCLUSIONS: Future trials should include clear population definitions, direct and indirect measures of the specific FSD construct, and procedures to allow generalizability of diagnosis and treatment to the target population.

Unconventional end points in cardiovascular clinical trials: should we be moving away from morbidity and mortality?

BACKGROUND: Mortality and irreversible or major morbid events are the end points conventionally chosen for cardiovascular clinical trials because they are considered to reflect the effects of intervention on the natural history of disease. Other end points are now being considered and implemented because of the recognized limitations associated with using mortality and morbidity as the sole measures of therapeutic efficacy. METHODS AND RESULTS: This article reflects the discussion and recommendations regarding nontraditional end points for cardiovascular trials generated from a meeting of clinical trial experts convened to discuss this issue. Less common end points that have been used in cardiovascular clinical trials include composite clinical scores integrating measures of quality of life with mortality and morbidity or using the function of vital organs as end points. Appropriate measurement and applications of such end points is controversial. CONCLUSIONS: More experience is needed in applying and analyzing results with these nontraditional end points to enable their optimal use in clinical trials in cardiology, but such approaches have the potential to redress many of the conceptual and actual deficiencies inherent in conventional measures of outcome.

An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation.

OBJECTIVE: To develop a contemporary, evidence-based definition of premature ejaculation (PE). METHODS: There are several definitions of PE; the most commonly quoted, the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders - 4th Edition - Text Revision, and other definitions of PE, are all authority-based rather than evidence-based, and have no support from controlled clinical and/or epidemiological studies. Thus in August 2007, the International Society for Sexual Medicine (ISSM) appointed several international experts in PE to an Ad Hoc Committee for the Definition of PE. The committee met in Amsterdam in October 2007 to evaluate the strengths and weaknesses of current definitions of PE, to critically assess the evidence in support of the constructs of ejaculatory latency, ejaculatory control, sexual satisfaction and personal/interpersonal distress, and to propose a new evidence-based definition of PE. RESULTS: The Committee unanimously agreed that the constructs which are necessary to define PE are rapidity of ejaculation, perceived self-efficacy, and control and negative personal consequences from PE. The Committee proposed that lifelong PE be defined as a male sexual dysfunction characterized by ejaculation which always or nearly always occurs before or within about one minute of vaginal penetration, and the inability to delay ejaculation on all or nearly all vaginal penetrations, and negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy. This definition is limited to men with lifelong PE who engage in vaginal intercourse. The panel concluded that there are insufficient published objective data to propose an evidence-based definition of acquired PE. CONCLUSION: The ISSM definition of lifelong PE represents the first evidence-based definition of PE. This definition will hopefully lead to the development of new tools and patient-reported outcome measures for diagnosing and assessing the efficacy of treatment interventions, and encourage ongoing research into the true prevalence of this disorder, and the efficacy of new pharmacological and psychological treatments.

An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine (ISSM) ad hoc committee for the definition of premature ejaculation.

INTRODUCTION: The medical literature contains several definitions of premature ejaculation (PE). The most commonly quoted definition, the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revision, and other definitions of PE are all authority based rather than evidence based, and have no support from controlled clinical and/or epidemiological studies. AIM: The aim of this article is to develop a contemporary, evidence-based definition of PE. METHODS: In August 2007, the International Society for Sexual Medicine (ISSM) appointed several international experts in PE to an Ad Hoc Committee for the Definition of Premature Ejaculation. The committee met in Amsterdam in October 2007 to evaluate the strengths and weaknesses of current definitions of PE, to critique the evidence in support of the constructs of ejaculatory latency, ejaculatory control, sexual satisfaction, and personal/interpersonal distress, and to propose a new evidence-based definition of PE. RESULTS: The committee unanimously agreed that the constructs that are necessary to define PE are rapidity of ejaculation, perceived self-efficacy and control, and negative personal consequences from PE. The committee proposed that lifelong PE be defined as ". . . a male sexual dysfunction characterized by ejaculation which always or nearly always occurs prior to or within about one minute of vaginal penetration, and the inability to delay ejaculation on all or nearly all vaginal penetrations, and negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy." This definition is limited to men with lifelong PE who engage in vaginal intercourse. The panel concluded that there are insufficient published objective data to propose an evidence-based definition of acquired PE. CONCLUSION: The ISSM definition of lifelong PE represents the first evidence-based definition of PE. This definition will hopefully lead to the development of new tools and Patient Reported Outcome measures for diagnosing and assessing the efficacy of treatment interventions and encourage ongoing research into the true prevalence of this disorder and the efficacy of new pharmacological and psychological treatments.