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Purpose To investigate the efficacy of high-dose vitamin D supplementation (VDS) plus standard urotherapy (SU) in managing pediatric overactive bladder dry (OAB-dry), specifically in children with (1) vitamin D levels between 20 and 35 ng/mL and (2) heightened baseline symptom severity. Methods In this secondary analysis of a randomized controlled trial, eligible children ( n  = 303) were assigned to 8 weeks of VDS + SU group, solifenacin (SOL) + SU group, or SU alone group. The primary outcome was voiding frequency; secondary outcomes included urgency, nocturia, quality of life (QoL), pediatric lower urinary tract symptoms scores, and patient satisfaction. Results Among 303 participants, 197 (65%) had vitamin D levels between 20 and 35 ng/mL, and 119 (39%) exhibited heightened baseline symptom severity. In both subgroups, VDS + SU resulted in significantly greater improvements in voiding frequency compared to SOL + SU and SU alone. In the vitamin D subgroup (20–35 ng/mL), the median difference in voids/day between VDS + SU and SOL + SU was 2.0 (95% CI, 1.0 to 3.0; P  = 0.003) and 3.2 compared to SU alone ( P  < 0.001). In the heightened symptom subgroup, the median difference was 3.0 (95% CI, 2.0 to 4.0; P  < 0.001) vs. SOL + SU and 5.0 (95% CI, 4.0 to 6.0; P  < 0.001) vs. SU alone. The VDS + SU group generally outperformed the other groups in various secondary outcome measures. Conclusion High-dose VDS plus SU has significant therapeutic benefit in children with OAB-dry in those with vitamin D levels between 20 and 35 ng/mL and with more severe symptoms, compared to SOL + SU or SU alone.

Available cholinergic drugs for treating Alzheimer's disease (AD) provide modest symptomatic benefit. We hypothesized that co-administration of a peripheral anticholinergic to reduce dose-limiting adverse effects (AEs) would enable the safe/tolerable use of higher cholinesterase inhibitor doses and thus improve their antidementia efficacy. A modified single-blind, ascending-dose, phase IIa study of donepezil plus solifenacin (CPC-201) lasting 26 weeks was conducted in 41 patients with probable AD of moderate severity. Entry criteria included the use of donepezil at a dose of 10 mg/day during the preceding 3 months. The primary outcome measure was the maximum tolerated dose (MTD) of donepezil achieved (to protocol limit of 40 mg/day) when administered with the anticholinergic solifenacin 15 mg/day. Secondary measures included assessments of cognitive and global function, as well as of AEs. The mean ± SD donepezil MTD increased to 38 ± 0.74 mg/day (median 40 mg/day; p < 0.001); 88% of the study population safely attained this dose at the end of titration. Markedly reduced donepezil AE frequency, especially gastrointestinal, allowed this dose increase. There were no drug-related serious AEs or clinically significant laboratory abnormalities. At 26 weeks, Alzheimer's Disease Assessment Scale Cognitive Component scores in the efficacy evaluable population improved by 0.35 ± 0.85 points over baseline (p < 0.05), an estimated 2.5 ± 0.84 points above 10 mg/day donepezil and 5.4 ± 0.84 points above historic placebo (both p < 0.05). Clinical Global Impression of Improvement scores improved by 0.94 ± 0.20 to 3.1 ± 0.20 points (p < 0.001). The findings suggest that limiting donepezil AEs by co-administration of solifenacin allows the safe administration of substantially higher cholinesterase inhibitors doses that may augment cognitive and global benefits in patients with AD.

Purpose This large dose-ranging study explored the benefits of different combinations of mirabegron and solifenacin on health-related quality of life (HRQoL), based on patient-reported outcomes (PROs), and patients (‘responders’) achieving clinically meaningful improvements in efficacy and HRQoL. Methods SYMPHONY (NCT01340027) was a Phase II, placebo- and monotherapy-controlled, dose-ranging, 12-week trial. Adult patients with overactive bladder (OAB) for ≥3 months were randomized to 1 of 12 groups: 6 combination (solifenacin 2.5/5/10 mg + mirabegron 25/50 mg), 5 monotherapy (solifenacin 2.5/5/10 mg, or mirabegron 25/50 mg), or placebo. Change from baseline to end of treatment was assessed, versus placebo and solifenacin 5 mg in: PROs (OAB-q [Symptom Bother/total HRQoL] and Patient Perception of Bladder Condition score), and responders achieving minimally important differences (MIDs) in PROs and predetermined clinically meaningful improvements in efficacy (e.g. <8 micturitions/24 h). Changes in PROs and responders were analysed using an ANCOVA model and logistic regression, respectively. Results The Full Analysis Set included 1278 patients. Combination therapy of solifenacin 5/10 mg + mirabegron 25/50 mg significantly improved PROs versus solifenacin 5 mg and placebo, and significantly more responders achieved MIDs in PROs and efficacy. Micturition frequency normalization was approximately twofold greater with 10 + 25 mg (OR 2.06 [95 % CI 1.11, 3.84; p  = 0.023]) and 5 + 50 mg (OR 1.91 [95 % CI 1.14, 3.21; p  = 0.015]) versus solifenacin 5 mg. Conclusion Combining mirabegron 25/50 mg and solifenacin 5/10 mg improves objective and subjective efficacy outcomes compared with placebo or solifenacin 5 mg.

The emergence of urinary retention (UR), specifically acute urinary retention (AUR), has been a concern when treating men with lower urinary tract symptoms (LUTS) with antimuscarinic drugs. In NEPTUNE (12-week, double-blind), men (≥45 years) with LUTS were randomized to receive tamsulosin oral-controlled absorption system (TOCAS) 0.4 mg, fixed-dose combination (FDC) of solifenacin (Soli) 6 mg + TOCAS 0.4 mg, FDC Soli 9 mg + TOCAS 0.4 mg, or placebo. In NEPTUNE II (40-week, open-label extension of NEPTUNE), continuing patients received 4-week FDC Soli 6 mg + TOCAS, then FDC Soli 6 mg or 9 mg + TOCAS for the remainder of the study, switchable every 3 months. Across both studies, 1208 men received ≥1 dose of FDC Soli 6 mg or 9 mg + TOCAS for up to 52 weeks; 1199 men completed NEPTUNE and 1066 received ≥1 dose in NEPTUNE II. In total, 13 men (1.1%; 95% CI, 0.6%-1.8%) reported a UR event while receiving FDC, eight of which were AUR (0.7%; 95% CI, 0.3%-1.3%, incidence 7/1000 man-years). Six men reported UR events while taking Soli 6 mg + TOCAS (three AUR), and seven men reported a UR event while taking Soli 9 mg + TOCAS (five AUR). One man developed AUR while taking TOCAS alone and four reported UR (three AUR) during placebo run-in. Most AUR/UR events occurred within 4 months of treatment initiation. FDC Soli and TOCAS was associated with a low rate of UR and AUR in men with LUTS.

Background Vasospastic angina (VSA) is characterized by coronary spasm, which can be aggravated by vasoactive substances such as serotonin. Hypothesis Sarpogrelate, a selective serotonin receptor antagonist, and high‐dose statin have some effects on the reduction of coronary spasm in patients with VSA. Methods We recruited 100 patients with angiographically confirmed VSA, and randomly assigned them into four groups: sarpogrelate with high‐dose statin (Group A, n = 25), sarpogrelate with low‐dose or no statin (Group B, n = 25), placebo with high‐dose statin (Group C, n = 25), and placebo with low‐dose or no statin (Group D, n = 25). The primary endpoint was the remission of coronary spasm on 1‐year follow‐up provocation test. Results The most common site of coronary spasm was left anterior descending artery (42%). Most patients (96%) took calcium channel blockers, and 46% were treated with vasodilators. Overall, 40% of patients reported no chest pain at 1 year, and 23% showed complete remission of coronary spasm on 1‐year follow‐up provocation test. No difference was observed in symptomatic and angiographically complete remission rate between the sarpogrelate and the placebo group. Although the apolipoprotein B level at the 1‐year follow‐up was significantly lower in the high‐dose statin group, symptomatic and angiographic outcomes were not different according to statin intensity. Distal thrombolysis in myocardial infarction (TIMI) flow on initial provocation test was independently associated with angiographically complete remission. Conclusions Sarpogrelate or high‐dose statin did not significantly improve the angiographic remission rate in patients with VSA. Distal TIMI flow on initial provocation test could predict the complete remission of coronary spasm at follow‐up.

Background Low-intensity shockwave therapy (Li-SWT) can improve bladder function through enhancement of angiogenesis and nerve regeneration and suppression of inflammation and overactivity. In this trial, we aimed to evaluate the efficacy of Li-SWT on persistent storage symptoms after transurethral surgery (TUS) for benign prostatic obstruction (BPO). Methods Between July 2020 and July 2022, 137 patients with persistent storage symptoms; urgency episodes/24 h ≥ 1 and daytime frequency ≥8, for at least three months after TUS for BPO were randomly allocated to Li-SWT versus sham versus solifenacin 10 mg/day in 3:1:1 ratio. The primary end point was the percent reduction from baseline in overactive bladder symptom score (OABSS) at 3-month follow-up. The changes in 3-day voiding diary parameters, quality of life (QoL) score, peak flow rate and residual urine at 3 and 6-month follow-up were compared. Treatment-related adverse effects were also evaluated. Results Baseline data were comparable between groups. The percent reduction from baseline in OABSS at 3-month follow-up was significantly higher in Li-SWT compared to sham (−55% versus −11%), and it was comparable between Li-SWT and solifenacin-10 (−55% versus −60%). Li-SWT achieved significant improvement like solifenacin-10 in 3-day voiding diary parameters and QoL score at 3-month follow-up. This improvement remained comparable between Li-SWT and solifenacin-10 at 6-month follow-up. No adverse effects related to Li-SWT were noted apart from tolerable pain during the procedure. Solifenacin-10 was associated with bothersome adverse effects in 73% of the patients with 11.5% discontinuation rate. Conclusions Li-SWT ameliorates persistent storage symptoms and promotes QoL after TUS for BPO, with comparable efficacy and better tolerance compared to solifenacin.

To the best of our knowledge, no studies have investigated the withdrawal strategy of pharmacological treatment with solifenacin or mirabegron in children diagnosed with urinary incontinence who have achieved continence on pharmacotherapy. The primary objective is to investigate if abrupt withdrawal versus gradual withdrawal of pharmacotherapy (solifenacin or mirabegron) influences the risk of recurrence of incontinence, assessed by a self-reported 14-day calendar of incontinence episodes. Children aged 5-14 years diagnosed with urinary incontinence, treated with pharmacotherapy of solifenacin or mirabegron and ready for withdrawal, will be randomized 1:1 to either abrupt or gradual withdrawal, according to the medical treatment that the child is receiving. The primary outcome measure is the recurrence of incontinence after withdrawal, 1 month after initiation of withdrawal of the physician-prescribed medication, assessed by a self-reported 14-day calendar of incontinence episodes. In addition, recurrence of incontinence after 3, 6, and 12 months after initiation of withdrawal will be measured. The hypothesis that gradual withdrawal is superior to abrupt withdrawal regarding the risk of recurrence of incontinence will be analyzed by logistic regression. Recruitment began at the end of May 2024 and will continue until 216 patients are included, which is expected by December 2027. As of February 2025, a total of 25 participants are included. The results are expected to influence the withdrawal strategy of pharmacological treatment with solifenacin or mirabegron in children with daytime urinary incontinence. ClinicalTrials.gov NCT06465576; https://clinicaltrials.gov/search?term=NCT06465576. DERR1-10.2196/63226.

According to International Children's Continence Society, the first-line treatment of children with daytime urinary incontinence is standard urotherapy, eventually followed by pharmacotherapy of anticholinergics. The effect of medical treatment is sparsely investigated and has been investigated primarily in nonrandomized trials. The primary objective of this trial is to evaluate if (1) combination therapy of solifenacin and mirabegron in low doses is superior to monotherapy of solifenacin in high dose and if (2) combination therapy of mirabegron and solifenacin in low doses is superior to monotherapy of mirabegron in high dose in the treatment of daytime urinary incontinence among children aged 5-14 years who are noncomplete responders to monotherapy of solifenacin in low dose or monotherapy of mirabegron in low dose. The secondary objective is to evaluate the treatment response of combination therapy of solifenacin and mirabegron in low doses, monotherapy in high doses, and monotherapy in low doses as supplementary comparisons. Additionally, the secondary objective is to evaluate the side effects, safety, and tolerability of the medical treatment as well as the effect of the treatment on the well-being and quality of life. Children aged 5-14 years diagnosed with daytime urinary incontinence refractory to standard urotherapy will be randomized 1:1:1:1 to 4 treatment groups. Initially, 2 groups will receive solifenacin 5 mg and 2 groups will receive mirabegron 25 mg. After 6 weeks, noncomplete responders will receive add-on treatments according to their primary randomization group. Group 1A will receive solifenacin 5 mg and add-on solifenacin 5 mg, group 1B will receive solifenacin 5 mg and add-on mirabegron 25 mg, group 2A will receive mirabegron 25 mg and add-on mirabegron 25 mg, and group 2B will receive mirabegron 25 mg and add-on solifenacin 5 mg. The total treatment period will be 18 weeks. The primary end point measure is treatment response assessed by change from visit 2 to the end of the study, according to the number of wet days per 7 days by DryPie. The BeDry study was approved by Clinical Trials in the European Union on June 12, 2024. Recruitment began on June 27, 2024, and will continue until 236 patients are included, which is expected to occur by September 2026. As of April 2025, 75 participants are included. This trial has the potential to optimize the medical treatment of children with daytime urinary incontinence, shorten the treatment period, diminish the side effects, and minimize unnecessary medical expenses. Clinical Trials in the European Union EUCT 2023-510187-13-00; https://tinyurl.com/2hva7ph8; ClinicalTrials.gov NCT06551246; https://clinicaltrials.gov/study/NCT06551246. PRR1-10.2196/63588.

Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring 1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite 2 . Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines 2 , including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase 2 , 3 , yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFE2L2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of IκBζ protein induction. The regulation of IκBζ is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17–IκBζ-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI–IκBζ regulatory axis could be an important new strategy for the treatment of IL-17–IκBζ-mediated autoimmune diseases. The immunoregulatory metabolite itaconate and its dimethyl derivative induce electrophilic stress and react with glutathione to induce both Nrf2-dependent and Nrf2-independent responses, resulting in AF3-mediated inhibition of the inflammation-related protein IκBζ.

Aims: To compare the pharmacokinetics, pharmacodynamics, and safety of sarpogrelate between controlled-release (CR) and immediate-release (IR) formulations after multiple-dose administration. Methods: This study was a randomized, open-label, 2-period, 2-treatment, crossover study in healthy subjects. All subjects received CR sarpogrelate 300 mg once daily and IR sarpogrelate 100 mg three times daily by random order each for 3 days with a 7-day washout period. Serial blood sampling was performed over 24 h. Pharmacokinetic parameters were determined by noncompartmental methods. Platelet aggregation to collagen, measured by light transmission aggregometry, was reported as maximal platelet aggregation. Results: Thirty-two subjects completed the study. CR sarpogrelate increased rapidly, reaching C max in 1.25 h (vs. 1.00 h in IR sarpogrelate) and declined with a t 1/2 of 3.59 h (vs. 1.12 h in IR sarpogrelate). The 90% CIs for the geometric mean ratio of AUC τ and C max,ss between IR and CR formulations were 1.18 to 1.40 and 0.99 to 1.29, respectively. The degree of inhibition of platelet aggregation was similar between two formulations. Conclusions: CR sarpogrelate showed slightly higher systemic exposure and similar peak concentration compared with IR sarpogrelate. The profiles of pharmacodynamics and safety were comparable between two formulations.