ObjectiveTo examine the safety and efficacy of mirabegron as 'add-on' therapy to solifenacin in patients with overactive bladder (OAB). Patients and MethodsThis multicentre, open-label, phase IV study enrolled patients aged ≥20 years with OAB, as determined by an OAB symptom score (OABSS) total of ≥3 points and an OABSS Question 3 score of ≥2 points, who were being treated with solifenacin at a stable dose of 2.5 or 5 mg once daily for at least 4 weeks. Study duration was 18 weeks, comprising a 2-week screening period and a 16-week treatment period. Patients meeting eligibility criteria continued to receive solifenacin (2.5 or 5 mg once daily) and additional mirabegron (25 mg once daily) for 16 weeks. After 8 weeks of treatment, the mirabegron dose could be increased to 50 mg if the patient's symptom improvement was not sufficient, if he/she was agreeable to the dose increase, and the investigator judged that there were no safety concerns. Safety assessments included adverse events (AEs), laboratory tests, vital signs, 12-lead electrocardiogram, QT corrected for heart rate using Fridericia's correction (QTcF) interval and post-void residual (PVR) volume. Efficacy endpoints were changes from baseline in OABSS total score, OAB questionnaire short form (OAB-q SF) score (symptom bother and total health-related quality of life [HRQL] score), mean number of micturitions/24 h, mean number of urgency episodes/24 h, mean number of urinary incontinence (UI) episodes/24 h, mean number of urgency UI episodes/24 h, mean volume voided/micturition, and mean number of nocturia episodes/night. Patients were instructed to complete the OABSS sheets at weeks À2, 0, 8 and 16 (or at discontinuation), OAB-q SF sheets at weeks 0, 8 and 16 (or at discontinuation) and patient voiding diaries at weeks 0, 4, 8, 12 and 16 (or at discontinuation). ResultsOverall incidence of drug-related treatment-emergent AEs (TEAEs) was 23.3%. Almost all TEAEs were mild or moderate. The most common TEAE was constipation, with similar incidence in the groups receiving a dose increase to that observed in the groups maintained on the original dose. Changes in PVR volume, QTcF interval, pulse rate and blood pressure were not considered to be clinically significant and there were no reports of urinary retention. Significant improvement was seen for changes in efficacy endpoints from baseline to end of treatment (EOT) in all groups (patients receiving solifenacin 2.5 or 5 mg + mirabegron 25 or 50 mg). ConclusionsAdd-on therapy with mirabegron 25 mg once daily for 16 weeks, with an optional dose increase to 50 mg at week 8, was well tolerated in patients with OAB treated with solifenacin 2.5 mg or 5 mg once daily. There were significant improvements from baseline to EOT in OAB symptoms with
Subcutaneous administration of capsaicin (5 mg/kg) immediately increased the temperature of the tail skin (Tsk) for 2 h in urethan-anesthetized rats, suggesting an increase in heat loss. O2 consumption, an index of heat production, also immediately increased after the capsaicin injection, and this increase lasted for >10 h. Colonic temperature (Tco) decreased within 1 h after the injection, and this decrease was followed by a long-lasting hyperthermic period. Adrenal demedullation largely attenuated the capsaicin-induced increase in O2consumption, and sympathetic denervation of the interscapular brown adipose tissue partly attenuated the increase in O2 consumption. However, capsaicin-induced heat loss was normal in these rats. In rats with cutaneous vasodilation maximized by warming and administration of hexamethonium, capsaicin did not further increase Tsk but normally induced heat production, and Tco gradually rose without a hypothermic period. Thus capsaicin simultaneously increased heat loss and heat production, and inhibition of one response did not affect the other. These findings suggest that capsaicin simultaneously activates independent networks for heat loss and heat production.
Background : Cognitive training in a laboratory improves car driving skills of older car drivers. However, it remains unclear whether other types of cognitive training at home have beneficial effects on driving skills. Using our developed cognitive training games that can be played on a television with a set-top box in a person’s home, we investigated the effects of a 6-week cognitive training program on driving skills, which included on-road evaluation (primary outcome), and cognitive functions and emotional states (secondary outcome) in older people. Methods : In this double-blinded randomized control trial (RCT), 60 older licensed drivers were randomly assigned into one of the two groups: a cognitive training game for car driving (CTCD) group and an active control cognitive training game (ACT) group. Participants in the CTCD group played the CTCD (processing speed, dual attention, and speed prediction) for 20 min in five sessions per week for 6 weeks. Participants in the ACT group played the ACT (selecting the larger number; selecting a number from largest to smallest; play a game of rock, article, scissors) for 20 min in five sessions per week for 6 weeks. We measured driving skills, various cognitive functions, and emotional states before and after the 6-week intervention period. Results : Our main results showed that compared to the ACT group, the CTCD group demonstrated improved driving skills (adjusted p = 0.034). Moreover, the CTCD group demonstrated improved inhibition (stroop, adjusted p = 0.042: reverse Stroop, adjusted p = 0.043) and processing speed performance symbol search (SS), adjusted p = 0.049; digit symbol coding (adjusted p = 0.047), compared to the ACT group. The CTCD group scored higher on vigor–activity mood (adjusted p = 0.041) as measured using the Profile of Mood State. Discussion : This randomized controlled trial provides scientific evidence for the benefits of the 6-week CTCD program on driving skills and cognitive functions, such as processing speed, inhibition, and vigor–activity mood, in healthy older people. Our results suggest that cognitive training is useful to improve the driving skills of older adults. Trial registration : This trial was registered at The University Hospital Medical Information Network Clinical Trials Registry (UMIN 000029769). Registered 31 October 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034010
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