IPSU

Impact of pelvic floor muscle training on sexual function of women with urinary incontinence and a comparison of electrical stimulation versus standard treatment (IPSU trial): a randomised controlled trial

Aims: To evaluate the clinical and cost-effectiveness of electric stimulation plus standard pelvic floor muscle training compared to standard pelvic floor muscle training alone in women with urinary incontinence and sexual dysfunction. Methods: Single centre two arm parallel group randomised controlled trial conducted in a Teaching hospital in England. Participants were women presenting with urinary incontinence and sexual dysfunction. The interventions compared were electric stimulation versus standard pelvic floor muscle training. Outcome measures: included Prolapse and Incontinence Sexual function Questionnaire (PISQ) physical function dimension at post-treatment (primary); other dimensions of PISQ, SF-36; EQ-5D, EPAQ, resource use, adverse events and cost-effectiveness (secondary outcomes). Results: 114 women were randomised (Intervention n=57; Control group n=57). 64/114 (56%). Participants: had valid primary outcome data at follow-up (Intervention 30; Control 34). The mean PISQ-PF dimension scores at follow-up were 33.1 (SD 5.5) and 32.3 (SD 5.2) for the Intervention and Control groups respectively; with the Control group having a higher (better) score. After adjusting for baseline score, BMI, menopausal status, time from randomisation and baseline oxford scale score the mean difference was -1.0 (95% CI: -4.0 to 1.9; P=0.474). There was no differences between the groups in any of the secondary outcomes at follow-up. Within this study, the use of electrical stimulation was cost-effective with very small incremental costs and quality adjusted life years (QALYs). Conclusions: In women presenting with urinary incontinence in conjunction with sexual dysfunction, physiotherapy is beneficial to improve overall sexual function. However no specific form of physiotherapy is beneficial over another. Trial registration ISRCTN09586238.

Distinct effects of IPSU and suvorexant on mouse sleep architecture

Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, SB-649868, suvorexant (MK-4305), and filorexant (MK-6096), have shown promise for the treatment of insomnias and sleep disorders. Whether antagonism of both OX1R and OX2R is necessary for sleep induction has been a matter of some debate. Experiments using knockout mice suggest that it may be sufficient to antagonize only OX2R. The recent identification of an orally bioavailable, brain penetrant OX2R preferring antagonist 2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (IPSU) has allowed us to test whether selective antagonism of OX2R may also be a viable strategy for induction of sleep. We previously demonstrated that IPSU and suvorexant increase sleep when dosed during the mouse active phase (lights off); IPSU inducing sleep primarily by increasing NREM sleep, suvorexant primarily by increasing REM sleep. Here, our goal was to determine whether suvorexant and IPSU affect sleep architecture independently of overall sleep induction. We therefore tested suvorexant (25 mg/kg) and IPSU (50 mg/kg) in mice during the inactive phase (lights on) when sleep is naturally more prevalent and when orexin levels are normally low. Whereas IPSU was devoid of effects on the time spent in NREM or REM, suvorexant substantially disturbed the sleep architecture by selectively increasing REM during the first 4 h after dosing. At the doses tested, suvorexant significantly decreased wake only during the first hour and IPSU did not affect wake time. These data suggest that OX2R preferring antagonists may have a reduced tendency for perturbing NREM/REM architecture in comparison with DORAs. Whether this effect will prove to be a general feature of OX2R antagonists vs. DORAs remains to be seen.

Kinetic properties of "dual" orexin receptor antagonists at OX1R and OX2R orexin receptors

Orexin receptor antagonists represent attractive targets for the development of drugs for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings and thorough investigations of pharmacokinetics and pharmacodynamics can predict contributing factors such as duration of action and undesirable effects. To this end, we studied the interactions between various "dual" orexin receptor antagonists and the orexin receptors, OX1R and OX2R, over time using saturation and competition radioligand binding with [(3)H]-BBAC ((S)-N-([1,1'-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide). In addition, the kinetics of these compounds were investigated in cells expressing human, mouse and rat OX1R and OX2R using FLIPR? assays for calcium accumulation. We demonstrate that almorexant reaches equilibrium very slowly at OX2R, whereas SB-649868, suvorexant, and filorexant may take hours to reach steady state at both orexin receptors. By contrast, compounds such as BBAC or the selective OX2R antagonist IPSU ((2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one) bind rapidly and reach equilibrium very quickly in binding and/or functional assays. Overall, the "dual" antagonists tested here tend to be rather unselective under non-equilibrium conditions and reach equilibrium very slowly. Once equilibrium is reached, each ligand demonstrates a selectivity profile that is however, distinct from the non-equilibrium condition. The slow kinetics of the "dual" antagonists tested suggest that in vitro receptor occupancy may be longer lasting than would be predicted. This raises questions as to whether pharmacokinetic studies measuring plasma or brain levels of these antagonists are accurate reflections of receptor occupancy in vivo.

The incidence of cyclic vomiting syndrome in children: population-based study

Objective: Cyclic vomiting syndrome (CVS) is characterized by severe recurrent episodes of vomiting in an otherwise healthy child. Currently, there is no population data on the incidence of CVS. The aim of this study was to determine the incidence of CVS and to define the clinical characteristics of the condition at diagnosis.
Methods: Each pediatrician on the island of Ireland was surveyed on a monthly basis from January 1, 2005 to December 31, 2005 by the Irish Pediatric Surveillance Unit (IPSU) and was asked to report any incident cases of CVS according to the criteria outlined by the First International Symposium on CVS. Subsequently, data on demographics and clinical features were collected anonymously from the reporting pediatricians.
Results: Eighty-nine percent (1,647 of 1,848) of the surveillance cards were returned, reporting 41 valid cases of CVS. The incidence of CVS in Ireland was 3.15/100,000 children per annum for 2005 (95% confidence interval [CI] 2.19-4.11). The median age at diagnosis of CVS was 7.42 yr (range 1.8-15 yr). The median age at onset of CVS was 4 yr (range 0.5-14 yr) with 46% (19 of 41) of children having an onset at or before the age of 3 yr. The median number of episodes of CVS per child per year was eight (range 3-52); the median duration of an episode was 24 h (range 1 h to 5 days). Of school-age children, 85% (22 of 26) had missed school in the previous year due to CVS and 44% (18 of 41) were admitted to hospital for supportive treatment or investigation of CVS.
Conclusion: CVS is a relatively common condition in pediatric patients, with an incidence comparable to other major gastrointestinal diseases of childhood, such as Crohn's disease. The onset of pediatric CVS is generally early in childhood and this disease causes significant morbidity in the majority of those affected.

Specific allergen immunotherapy use in 2012: an Irish Paediatric Surveillance Unit (IPSU) study

Specific immunotherapy (SIT) is a disease modifying treatment for allergic rhinitis (AR), with its benefits most evident in those who are refractory to medical treatment. It is used less frequently in UK than Europe/US. No data exist on SIT use in Ireland. We audited paediatric practice to evaluate patient selection, SIT modalities and adverse events (A.E.). A 9 item questionnaire was sent to Irish paediatricians, identified via the Irish Paediatric Surveillance Unit (IPSU) mailing list. 58 children have undertaken SIT (Subcutaneous SCIT =3, Sublingual = 55). This represents 0.01% of Irish children estimated to have AR. 33 (56%) had asthma; 18 (55%) had perennial asthma, 7 (21%) seasonal asthma. Adverse events occurred in 5 cases (8.6%). Three treatments (3-5%) were discontinued as a result. SIT is available across Ireland, though only extremely small numbers of children with AR are being treated yet. Co-morbid asthma is frequent and does not increase adverse events. This audit will raise awareness of SIT use for AR in Ireland.