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.

Psychosexual therapy for delayed ejaculation based on the Sexual Tipping Point model.

The Sexual Tipping Point(®) (STP) model is an integrated approach to the etiology, diagnosis and treatment of men with delayed ejaculation (DE), including all subtypes manifesting ejaculatory delay or absence [registered trademark owned by the MAP Educational Fund, a 501(c)(3) public charity]. A single pathogenetic pathway does not exist for sexual disorders generally and that is also true for DE specifically. Men with DE have various bio-psychosocial-behavioral & cultural predisposing, precipitating, maintaining, and contextual factors which trigger, reinforce, or worsen the probability of DE occurring. Regardless of the degree of organic etiology present, DE is exacerbated by insufficient stimulation: an inadequate combination of "friction and fantasy". High frequency negative thoughts may neutralize erotic cognitions (fantasy) and subsequently delay, ameliorate, or inhibit ejaculation, while partner stimulation (friction) may prove unsatisfying. Assessment requires a thorough sexual history including inquiry into masturbatory methods. Many men with DE engage in an idiosyncratic masturbatory style, defined as a masturbation technique not easily duplicated by the partner's hand, mouth, or vagina. The clinician's most valuable diagnostic tool is a focused sex history (sex status). Differentiate DE from other sexual problems and review the conditions under which the man can ejaculate. Perceived partner attractiveness, the use of fantasy during sex, anxiety-surrounding coitus and masturbatory patterns require meticulous exploration. Identify important DE causes by juxtaposing an awareness of his cognitions and the sexual stimulation experienced during masturbation, versus a partnered experience. Assist the man in identifying behaviors that enhance immersion in excitation and minimize inhibiting thoughts, in order to reach ejaculation in his preferred manner. Discontinuing, reducing or altering masturbation is often required, which evokes patient resistance. Coaching tips are offered on how to ensure adherence to this suspension, manage resistance and facilitate success. Depending on motivation level, masturbation interruption may be compromised and negotiated. Encourage a man who continues to masturbate to alter style ("switch hands") and to approximate the stimulation likely to be experienced with his partner. Success will require most men to be taught to learn bodily movements and fantasies that approximate the thoughts and sensations experienced in masturbation. Fertility issues, as well as patient/partner anger are important causational factors, which often require individual and/or conjoint consultation. Drug treatment would benefit men particularly with severe DE, regardless of concomitant psychosocial-behavioral and cultural complications. When and if a safe effective medication for DE becomes available, this author's transdisciplinary perspective supports appropriate medication use when integrated with counseling. This approach emphasizes the utility of a biopsychosocial-cultural perspective combined with special attention to the patient's narrative. Treatment is patient-centered, holistic and integrates a variety of therapies as needed.

Efficacy, safety, and tolerability of fentanyl pectin nasal spray in patients with breakthrough cancer pain.

OBJECTIVE: Assessment of analgesic effectiveness, safety, and tolerability of fentanyl pectin nasal spray (FPNS) in the treatment of breakthrough cancer pain (BTcP) in routine clinical practice. METHODS: A prospective, open-label, noninterventional study (4-week observation period, 3 month follow-up) of opioid-tolerant adults with BTcP in 41 pain and palliative care centers in Germany. Standardized BTcP questionnaires and patient diaries were used. Evaluation was made of patient-reported outcomes with respect to "time to first effect", "time to maximum effect", BTcP relief, as well as changes in BTcP-related impairment of daily life activities, quality-of-life restrictions, and health care resource utilization. RESULTS: A total of 235 patients were recruited of whom 220 completed all questionnaires and reported on 1,569 BTcP episodes. Patients reported a significant reduction of maximum BTcP intensity (11-stage numerical rating scale [0= no pain, 10= worst pain conceivable]) with FPNS (mean ± standard deviation = 2.8±2.3) compared with either that reported at baseline (8.5±1.5), experienced immediately before FPNS application (7.4±1.7), or that achieved with previous BTcP medication (6.0±2.0; P<0.001 for each comparison). In 12.3% of BTcP episodes, onset of pain relief occurred ≤2 minutes and in 48.4% ≤5 minutes; maximum effects were reported within 10 minutes for 37.9% and within 15 minutes for 79.4%. By the end of the study, there had been significant improvements versus baseline in BTcP-related daily life activities (28.3±16.9 vs 53.1±11.9), physical (35.9±8.4 vs 26.8±6.5), and mental quality of life (38.7±8.5 vs 29.9±7.9) (P<0.001 for each comparison vs baseline); in addition, health care resource utilization requirements directly related to BTcP were reduced by 67.5%. FPNS was well tolerated; seven patients (3.2%) experienced eight treatment-emergent adverse events of which none was serious. There were no indicators of misuse or abuse. CONCLUSION: FPNS provided rapid and highly effective BTcP relief in opioid-tolerant cancer patients with substantial improvements in daily functioning and quality of life. FPNS was well tolerated and associated with significant reductions in health care resource utilization and nursing assistance.

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.

Relationship between onset of pain relief and patient satisfaction with fentanyl pectin nasal spray for breakthrough pain in cancer.

BACKGROUND: Satisfaction with pain relief in patients with breakthrough pain in cancer (BTPc) has typically been assessed by overall efficacy without consideration of the rapidity of that response. OBJECTIVE: To determine the relationship between speed of onset of pain relief and patient satisfaction for treated BTPc episodes overall and for individual treatments. DESIGN: Pooled data from two randomized, double-blinded crossover studies. SETTING/SUBJECTS: Patients having 1-4 BTPc episodes per day on ≥60 mg/day oral morphine or equivalent. Episodes treated with fentanyl pectin nasal spray (FPNS; 100-800 µg), immediate-release morphine sulfate (IRMS), or placebo. MEASUREMENTS: Pain intensity was measured on an 11-point scale (5-60 minutes posttreatment); satisfaction was measured on a 4-point scale (30 and 60 minutes). The primary analysis assessed the overall relationship of time to onset of pain relief (pain intensity difference [PID]≥1) or time to clinically meaningfully reduction in pain (PID≥2) versus patient satisfaction and overall pain intensity (summed pain intensity difference at 30 [SPID30] and 60 minutes [SPID60]) assessed by analysis of variance (ANOVA). A secondary analysis assessed whether satisfaction was different between treatments using a within-patient comparison. RESULTS: Eight hundred thirty-one FPNS-treated, 368 IRMS-treated, and 200 placebo-treated episodes were analyzed. Overall, within the pool there was a statistically significant relationship between time to onset of pain relief (PID≥1 and PID≥2) and patient satisfaction (both speed of relief and overall) at 30 and 60 minutes (p<0.001); this relationship was also true within individual treatment groups (p<0.01). Similar results were found for overall pain intensity reduction. When treatment groups were compared using within-patient data, FPNS provided earlier onset of pain relief than IRMS or placebo (p<0.05), which translated into better satisfaction at 60 minutes (p<0.01). CONCLUSIONS: Earlier onset of pain relief resulted in greater patient satisfaction and overall relief of pain; between-treatment comparisons showed that FPNS provided earlier pain relief and greater satisfaction than IRMS or placebo.

An analysis of the variability of breakthrough pain intensity in patients with cancer.

BACKGROUND: The management of breakthrough pain in patients with cancer (BTPc) generally includes an initial titration of breakthrough pain medication to an effective dose, followed by the use of that dose in all subsequent episodes. This strategy presumes that an individual patient has a degree of consistency of pain during repeat episodes; however, that presumption has not been formally assessed. OBJECTIVE: To examine the variation in pain intensity of BTPc episodes within individual patients and across patients. METHODS: Data were pooled from 2 randomized, double-blind, crossover studies that used fentanyl pectin nasal spray (FPNS) vs comparator to relieve BTPc. Eligible patients were adults with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and adequately controlled background pain. The FPNS dose was titrated prior to a double-blind treatment consisting of 10 episodes. Pain intensity was reported on an 11-point numeric scale in which 0 = no pain and 10 = worst possible pain. Inter- and intrapatient variabilities of baseline pain intensity scores per episode were analyzed by analysis of covariance via a mixed-effect model. The influences of demographics and ECOG grade at study entry were assessed. RESULTS: Mean baseline pain intensity score was 7.3 (standard deviation, 1.76; range, 2-10) across 1,399 BTPc episodes in 152 patients. The interpatient variability of baseline pain intensity scores was 75.96%; intrapatient variability was 20.64%. Fixed terms for demographics and ECOG grade did not significantly influence baseline pain intensity score (≤ 5% level). LIMITATIONS: This was a post hoc analysis. CONCLUSIONS: Baseline pain intensity scores during episodes of BTPc vary widely between patients, but vary little within individual patients; this supports the use of a consistent maintenance dosage of analgesia for BTPc, once it has been titrated to an effective dose. FUNDING/SUPPORT: The study was funded by Archimedes Development Ltd.

A report on the long-term use of fentanyl pectin nasal spray in patients with recurrent breakthrough pain.

CONTEXT: As patients with cancer are living longer, there is a need to ensure that treatments used for palliative care are well tolerated and effective during long-term use. OBJECTIVES: To investigate the long-term use of fentanyl pectin nasal spray (FPNS) for the treatment of breakthrough pain in cancer (BTPc) in patients receiving regular opioid therapy. METHODS: Adult patients (N = 401) taking at least 60 mg/day oral morphine or equivalent, experiencing one to four episodes of BTPc a day, entered an open-label long-term study (NCT00458510). Patients had either completed an FPNS randomized controlled trial or were newly identified. Of these, 171 patients continued into an extension study. Up to four episodes of BTPc a day were treated with FPNS at 100-800 µg titrated doses. During the extension study, patients visited the clinic every four weeks for assessment and reporting of adverse events (AEs). RESULTS: There were 163 patients with documented FPNS use. The mean duration of use was 325 days; 46 patients used FPNS for ≥360 days; the maximum duration was 44 months. Seventy percent of patients did not change their FPNS dose; 2% of patients withdrew from the study because of the lack of efficacy. The most common AEs, aside from disease progression, were insomnia, 9.9%; nausea, 9.4%; vomiting, 9.4%; and peripheral edema, 9.4%. The overall incidence of FPNS-related AEs was 11.1%, the most common being constipation (4.1%), with no apparent dose relationship. Ten patients (5.8%) experienced nasal AEs, most of which were mild or moderate. CONCLUSION: FPNS appeared to provide sustained benefit and was well tolerated during long-term treatment of BTPc.

Chitosan: a promising safe and immune-enhancing adjuvant for intranasal vaccines.

The nasal route is attractive for the delivery of vaccines in that it not only offers an easy to use, non-invasive, needle-free alternative to more conventional parenteral injection, but it also creates an opportunity to elicit both systemic and (crucially) mucosal immune responses which may increase the capability of controlling pathogens at the site of entry. Immune responses to "naked" antigens are often modest and it is widely accepted that incorporation of an adjuvant is a prerequisite for the achievement of clinically effective nasal vaccines. Many existing adjuvants are sub-optimal or unsuitable because of local toxicity or poor enhancement of immunogenicity. Chitosan, particularly chitosan salts, have now been used in several preclinical and clinical studies with good tolerability, excellent immune stimulation and positive clinical results across a number of infections. Particularly significant evidence supporting chitosan as an adjuvant for nasal vaccination comes from clinical investigations on a norovirus vaccine; this demonstrated the ability of chitosan (ChiSys®), when combined with monophosphoryl lipid, to evoke robust immunological responses and confer protective immunity following (enteral) norovirus challenge. This article summarizes the totality of the meaningful information (including key unpublished data) supporting the development of chitosan-adjuvanted vaccines.

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.

A psychological perspective on male rejuvenation.

Male rejuvenation, defined as a process in men to both limit the impact of aging on body image and experience greater virility, is growing among middle-aged and older men. While rejuvenation was primarily in the domain of the younger male athlete with the use of performance enhancing hormones or in the aging woman through the use of cosmetic surgery, it is now more common among middle-aged and older men. Male rejuvenation can occur both through aesthetic surgical means and hormonal manipulation through anabolic steroid use. In this article, the authors review the psychological issues and perceptions surrounding male aesthetic surgeries and the resulting alteration of perception by peers and family; highlight the motives and desires behind the use of anabolic hormones at often supra-physiologic levels, and the intent to improve body image; and clarify the needs that remain to be examined in future research in this field.