Dapoxetine for the Treatment of Premature Ejaculation: Results from a Randomized,Double-Blind,Placebo-Controlled Phase 3 Trial in 22 Countries

Background

Dapoxetine is being developed for the on-demand treatment of premature ejaculation (PE). Previous clinical trials have demonstrated its safety and efficacy.

Objective

To evaluate the long-term efficacy and safety of dapoxetine in men with PE.

Design, setting, and participants

This randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial, conducted in 22 countries, enrolled men (N = 1162) ≥18 yr of age who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for PE for ≥6 mo, with an intravaginal ejaculatory latency time (IELT) ≤2 min in ≥75% of intercourse episodes at baseline.

Intervention

Dapoxetine 30 mg or dapoxetine 60 mg or placebo on demand (1–3 h before intercourse) for 24 wk.

Measurements

Stopwatch-measured IELT, Premature Ejaculation Profile (PEP), Clinical Global Impression (CGI) of change, adverse events (AEs).

Results and limitations

The study was completed by 618 men. Mean average IELT increased from 0.9 min at baseline (all groups) to 1.9 min, 3.2 min, and 3.5 min with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively, at study end point; geometric mean IELT increased from 0.7 min at baseline to 1.1 min, 1.8 min, and 2.3 min, respectively, at study end point. All PEP measures and IELTs improved significantly with dapoxetine versus placebo at week 12 and week 24 (p < 0.001 for all). The most common AEs were nausea, dizziness, diarrhea, and headache. AEs led to discontinuation in 1.3%, 3.9%, and 8.2% of subjects with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively. Limitations of this study included the exclusion of men who were not in long-term monogamous relationships.

Conclusions

Dapoxetine significantly improved all aspects of PE and was generally well tolerated in this broad population.     

Orexin Neurons Are Necessary for the Circadian Control of REM Sleep

Study Objectives:

The orexin-producing neurons are hypothesized to be essential for the circadian control of sleep/wake behavior, but it remains unknown whether these rhythms are mediated by the orexin peptides or by other signaling molecules released by these neurons such as glutamate or dynorphin. To determine the roles of these neurotransmitters, we examined the circadian rhythms of sleep/wake behavior in mice lacking the orexin neurons (ataxin-3 [Atx] mice) and mice lacking just the orexin neuropeptides (orexin knockout [KO] mice).

Design:

We instrumented mice for recordings of sleep-wake behavior, locomotor activity (LMA), and body temperature (T_b) and recorded behavior after 6 days in constant darkness.

Results:

The amplitude of the rapid eye movement (REM) sleep rhythm was substantially reduced in Atx mice but preserved in orexin KO mice. This blunted rhythm in Atx mice was caused by an increase in the amount of REM sleep during the subjective night (active period) due to more transitions into REM sleep and longer REM sleep episodes. In contrast, the circadian variations of T_b, LMA, Wake, non-REM sleep, and cataplexy were normal, suggesting that the circadian timekeeping system and other output pathways are intact in both Atx and KO mice.

Conclusions:

These results indicate that the orexin neurons are necessary for the circadian suppression of REM sleep. Blunting of the REM sleep rhythm in Atx mice but not in orexin KO mice suggests that other signaling molecules such as dynorphin or glutamate may act in concert with orexins to suppress REM sleep during the active period.

Citation:

Kantor S; Mochizuki T; Janisiewicz AM; Clark E; Nishino S; Scammell TE. Orexin neurons are necessary for the circadian control of REM sleep. SLEEP 2009;32(9):1127-1134.     

Polysomnographic and Health-related Quality of Life Correlates of Restless Legs Syndrome in the Sleep Heart Health Study

Study Objectives:

Sleep disturbance is the primary clinical morbidity of restless legs syndrome (RLS). To date, sleep disturbance in RLS has been measured in (1) clinical samples with polysomnography (PSG) or (2) population-based samples by self-report. The objective of this study was to analyze sleep by PSG in a population-based sample with symptoms of RLS.

Design:

Cross-sectional observational study

Setting:

Community-based

Participants:

3433 older men and women

Interventions:

None

Measurements and Results:

RLS was evaluated using an 8-item self-administered questionnaire based on NIH diagnostic criteria and required symptoms occurring ≥ five times per month and associated with at least moderate distress. Health-related quality of life (HRQOL) was determined using the SF-36. Unattended, in-home PSG was performed. Data were assessed using general linear models with adjustment for demographic, health-related variables, and apnea-hypopnea index (AHI). Subjects with RLS had longer adjusted mean sleep latency (39.8 vs 26.4 min, P < 0.0001) and higher arousal index (20.1 vs 18.0, P = 0.0145) than those without RLS. Sleep latency increased progressively as the frequency of RLS symptoms increased from 5-15 days per month to 6-7 days per week. No differences in sleep stage percentages were observed between participants with and without RLS. Subjects with RLS also reported poorer HRQOL in all physical domains as well as in the Mental Health and Vitality domains.

Conclusions:

These novel PSG data from a nonclinical, community-based sample of individuals with RLS document sleep disturbance in the home even in individuals with intermittent symptoms.

Citation:

Winkelman JW; Redline S; Baldwin CM; Resnick HE; Newman AB; Gottlieb DJ. Polysomnographic and health-related quality of life correlates of restless legs syndrome in the sleep heart health study. SLEEP 2009;32(6):772-778.     

青少年胫后神经皮层体感诱发电位正常参考值研究

目的探讨及建立青少年胫后神经皮层体感诱发电位正常参考值范围。方法对45名13～24岁健康青少年记录和测量胫后神经皮层体感诱发电位P40、N50及P60的正常值。建立多元回归模型,探讨性别、年龄及身高等生理因素对峰潜伏期的影响。结果所有45例受试者均检测出可清晰辨认的波形。左右侧峰潜伏期差值无明显差异,与性别、年龄及身高无关。P40、N50、P60的峰潜伏期与身高呈XEN关（r=0.766～0．896,P〈0．001）,与年龄及性别无关。结论青少年胫后神经皮层体感诱发电位各波峰潜伏期正常参考值及上限标准可根据峰潜伏期与身高的回归方程确定。     

Comparison of clinical characteristics among narcolepsy with and without cataplexy and idiopathic hypersomnia without long sleep time, focusing on HLA-DRB11501/DQB10602 finding

BackgroundClinical characteristics of narcolepsy without cataplexy (NA w/o CA) and its relation to positivity of HLA-DRB1¹1501/DQB1¹0602 remain unclarified. We investigated clinical features of NA w/o CA, particularly addressing HLA-DRB1¹1501/DQB1¹0602.MethodsComparisons of the Epworth Sleepiness Scale (ESS), multiple sleep latency test (MSLT) variables, rapid eye movement (REM)-related symptoms, and treatment response to psychostimulant medication were made for four patient groups (narcolepsy with cataplexy; NA–CA, NA w/o CA HLA-positive, NA w/o CA HLA-negative, and idiopathic hypersomnia without long sleep time; IHS w/o LST).ResultsMean sleep latency was significantly shorter and the rate of reduction of ESS after medication was lower in both NA–CA and NA w/o CA HLA-positive groups than those in the IHS w/o LST group. Among the three narcoleptic groups, the NA w/o CA HLA-negative group showed the lowest REM latency and the highest reduction rate of ESS after treatment. Neither these subjective and objective sleepiness measures nor the treatment response measure was significantly different between this group and the IHS w/o LST group.ConclusionsIn NA w/o CA, HLA-positivity might affect hypersomnia severity and REM propensity. The NA w/o CA HLA-negative group and the IHS w/o LST group exhibit equivalent hypersomnia severity.     

内囊出血家兔短潜伏期体感诱发电位的改变

目的:探讨内囊出血对短潜伏期体感诱发电位的影响。方法:立体定向注射自体动脉血制备家兔内囊出血动物模型,观察内囊出血前后家兔脑组织的病理形态学变化;短潜伏期体感诱发电位(SLSEP)的改变。结果:家兔内囊出血后,脑组织出现明显的占位血肿;造模后不同时点,SLSEP中P1-N1的峰间潜伏期较出血前均明显延长(P<0.01);N2-P1峰-峰值较出血前均明显减小(P<0.01)。结论:内囊出血可阻碍神经冲动传导,从而导致SLSEP中P1-N1的峰间潜伏期延长;N2-P1峰-峰值减小。     

The amplitude of lower leg motor evoked potentials is a reliable measure when controlled for torque and motor task

OBJECTIVES: Motor evoked potential (MEP) amplitudes have the disadvantage of a high variability when repeatedly assessed. This affects the reliability of MEP amplitude measurements taken during the course of motor incomplete spinal cord injury (iSCI). The study investigated the reliability of anterior tibial (TA) MEP measures controlled for dorsal flexion torque and motor task. METHODS: TA MEPs were recorded at 10, 20, 40 and 60% of maximal voluntary contraction (MVC) during a static and dynamic (isometric increase of dorsal flexion torque) motor task. To determine reliability, 20 healthy and five chronic iSCI subjects were tested twice (> or =7 days) by the same investigator. Intraclass correlation coefficients (ICCs) were calculated. MEP amplitudes and latencies were compared between 20 healthy and 29 iSCI subjects. RESULTS: The reliability of MEP amplitude was in general good (ICC > or = 0.52) and was highest during the static task at 40% MVC (ICC = 0.77). The increased facilitation by the dynamic motor task showed the best reliability at 20% MVC (ICC = 0.48). The reliability was good to excellent for MEP latency (0.46 < or = ICC < or = 0.81), MVC (ICC > or = 0.90) and for the TMS threshold required to evoke a MEP response (ICC > or = 0.77). The torque generated by the MEP response ()0.02 < or = ICC < or = 0.55) and the duration of the silent period (0.07 < or = ICC < or = 0.50) were not reliable. Both MEP amplitudes and latencies differed significantly between healthy and iSCI subjects. CONCLUSIONS: Controlling for torque generation and motor task establishes a reliability of TA MEP amplitudes that is sufficient for longitudinal assessments in motor incomplete SCI.     

Validity and power in hemodynamic response modeling: a comparison study and a new approach

One of the advantages of event-related functional MRI (fMRI) is that it permits estimation of the shape of the hemodynamic response function (HRF) elicited by cognitive events. Although studies to date have focused almost exclusively on the magnitude of evoked HRFs across different tasks, there is growing interest in testing other statistics, such as the time-to-peak and duration of activation as well. Although there are many ways to estimate such parameters, we suggest three criteria for optimal estimation: 1) the relationship between parameter estimates and neural activity must be as transparent as possible; 2) parameter estimates should be independent of one another, so that true differences among conditions in one parameter (e.g., hemodynamic response delay) are not confused for apparent differences in other parameters (e.g., magnitude); and 3) statistical power should be maximized. In this work, we introduce a new modeling technique, based on the superposition of three inverse logit functions (IL), designed to achieve these criteria. In simulations based on real fMRI data, we compare the IL model with several other popular methods, including smooth finite impulse response (FIR) models, the canonical HRF with derivatives, nonlinear fits using a canonical HRF, and a standard canonical model. The IL model achieves the best overall balance between parameter interpretability and power. The FIR model was the next-best choice, with gains in power at some cost to parameter independence. We provide software implementing the IL model.     

Efficacy and tolerability of indiplon in older adults with primary insomnia

OBJECTIVE: To evaluate the efficacy and safety of indiplon in elderly patients with primary insomnia. PATIENTS AND METHODS: Elderly patients, 65-80 years (N=358; 55% female; mean age, 71 years) who met the criteria for primary insomnia according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) for three months were randomized to two weeks of double-blind nightly treatment with 5 mg or 10 mg indiplon or placebo. Daily self-assessments by the patients included latency to sleep onset (LSO), total sleep time (TST), number of awakenings (NAW), wake time after sleep onset (WASO), and sleep quality. Data were collected between July, 2002, and October, 2003, at 52 clinical research sites in North America. RESULTS: Treatment with indiplon was associated with significant reduction in LSO at Week 1 for the 5 mg (34.6+/-1.8 min) and 10 mg doses (30.4+/-1.6 min) relative to placebo (47.4+/-2.5 min; p<0.0001 for both comparisons). During Week 2, LSO remained shorter on both indiplon doses compared to placebo (5 mg, p=0.016; and 10 mg, p=0.0028). During both study weeks, treatment with indiplon was also associated with significant improvement, relative to placebo, in TST, NAW, WASO, and sleep quality. The frequency of adverse events was similar in the indiplon 5 mg and placebo groups; somnolence, nausea, depression and decreased appetite were slightly more common in the indiplon 10 mg group. CONCLUSION: In elderly patients with primary insomnia, indiplon 5 mg and 10 mg were efficacious in inducing and maintaining sleep and improving sleep quality during the two weeks of treatment. Indiplon 5mg was well-tolerated, with no serious adverse events and no significant changes in electrocardiogram (ECG) or routine clinical laboratory evaluations; the 10mg dose produced slightly greater efficacy as well as somewhat increased adverse events.     

Steady-state visually evoked potential topography during processing of emotional valence in healthy subjects

The International Affective Picture System (IAPS) is increasingly used in brain imaging studies to examine emotional processes. This task allows valence and arousal content to be systematically investigated; however, previous studies have generally failed to select images that vary in one dimension as well as hold constant the variability on the other dimension. In addition, no studies have investigated the temporal structure associated with the conscious, ongoing processing of emotional stimuli following systematic selection of IAPS images. The aim of the present study was therefore to use steady-state probe topography (SSPT) to examine the steady-state visually evoked potentials (SSVEPs) associated with the processing of pleasant and unpleasant images low in arousal content. Seventy-five IAPS images, categorized as unpleasant, neutral, or pleasant, were presented to 16 healthy subjects while brain activity was recorded from 64 scalp sites. Analysis subtracted the activity associated with the presentation of neutral images from the activity associated with the presentation of pleasant as well as unpleasant images. Results demonstrate that both pleasant and unpleasant valence is associated with transient, widespread, and bilateral frontal SSVEP latency reductions. Unpleasant images were also associated with a transient bilateral anterior frontal amplitude decrease. Latency reductions are interpreted as increases in neural information processing speed, while amplitude reductions are interpreted in the current paper as analogous to an event-related desynchronisation commonly associated with the alpha bandwidth. These key findings support previous literature in terms of there being substantial overlap in frontal neural circuitry when the brain processes pleasant and unpleasant valence relative to neutral valence.