Obstructive sleep apnea (OSA) is a common sleep disorder associated with substantial cardiovascular morbidity and mortality. Although positive airway pressure (PAP) remains the gold-standard treatment, poor long-term adherence often limits its clinical effectiveness, underscoring the need for safe and effective pharmacological alternatives. Advances in the understanding of OSA endotypes, including anatomical collapsibility, upper airway muscle responsiveness, arousal threshold, and loop gain, have shifted research toward precision pharmacotherapy. Early studies of single-agent therapies, such as protriptyline and acetazolamide, were limited by modest efficacy or clinically significant adverse effects. More recent dual-drug combinations and anti-obesity medications have shown greater promise. In particular, atomoxetine plus oxybutynin has demonstrated significant reductions in the apnea-hypopnea index (AHI) by enhancing upper airway muscle tone across sleep stages. In parallel, glucagon-like peptide-1 receptor agonists have substantially changed the management of obesity-related OSA. Tirzepatide, in particular, has produced marked weight loss of nearly 20% and an AHI reduction of more than 50%, leading to its recent U.S. Food and Drug Administration approval for OSA. Despite earlier skepticism, the shift from broad-spectrum agents toward endotype-specific and metabolic-targeted therapies may improve the management of selected patients with OSA. However, long-term safety and cost-effectiveness require further evaluation before these emerging pharmacological options can be broadly integrated into care for patients who cannot tolerate conventional PAP therapy.

Around one-third of patients with monosymptomatic nocturnal enuresis (MNE) do not respond to conventional first-line treatments. Although international guidelines outline second- and third-line treatment options, these recommendations may not fully address the needs of every case encountered in daily practice. Therefore, the question of which treatment strategy should be used for refractory cases remains unanswered. We conducted a scoping review (PROSPERO CRD420251171197) following PRISMA Extension for Scoping Reviews (PRISMA-ScR), searching the PubMed, Embase, Ovid MEDLINE, Scopus, Web of Science, Google Scholar, CINAHL and the Cochrane Library databases to identify all published reports of treatment for refractory MNE in paediatric patients up to March 2026. Eligible studies included randomized controlled trials and prospective or retrospective observational cohort studies written in English. The primary outcome was the number of wet nights (classified as complete, partial or no response according to the ICCS criteria). Secondary outcomes included a comparison of the efficacy of second- and third-line treatment options if enough data could be found. The Cochrane RoB 2 tool was used to assess the risk of bias in randomized clinical trials, and the Methodological Index for Non-Randomized Studies (MINORS) was used for non-randomized cohort studies. Following screening and eligibility assessment, 17 out of 2578 articles met the PICO inclusion criteria. The included studies enrolled a total of 1348 children and adolescents with mean ages ranging from approximately 8 to 17 years. Many of the second- or third-line treatments described in the literature were excluded due to incorrect methodology, study design or patient population. The results showed that, following first-line treatment, a combination of biofeedback, electrical nerve stimulations, anticholinergics (e.g. oxybutynin, tolterodine, solifenacin), β3-adrenoceptor agonists (e.g. vibegron), tricyclic antidepressants (e.g. imipramine) and selective serotonin reuptake inhibitor (e.g. fluoxetine) improved both partial response (PR) and complete response (CR) at varying rates across highly heterogeneous interventions and study populations. However, the evidence does not strongly support a treatment algorithm. Furthermore, reports on electro-acupuncture, furosemide, onabotulinumtoxin A injections or the herbal medicine 'shokenchuto' were considered unreliable for pure refractory MNE, despite improvements in PR and CR occurring at different rates. Conclusion: The question of which treatment strategy should be used for refractory cases remains unanswered due to a lack of sufficiently unbiased, prospective, randomized, controlled studies involving long-term follow-up. Some second- and third-line treatment options may improve PR and CR rates, despite the limited available evidence to support a treatment algorithm. However, further research is needed to confirm these benefits.

Polypharmacy, the concurrent use of multiple medications, is increasingly prevalent in older people and is associated with adverse outcomes such as falls, frailty, functional, and cognitive decline, and increased hospitalization and mortality. The liver, as the primary site of metabolism, is exposed to varying drug concentrations during first pass metabolism, hepatic clearance and perfusion, potentially causing alterations in liver sinusoidal endothelial cells (LSEC). LSEC are specialized endothelial cells responsible for maintaining fenestrations-dynamic, transcellular pores that facilitate the exchange of substances between the blood and liver parenchyma. Disruption of fenestrations can compromise liver function, contributing to a variety of hepatic disorders. This study investigated the effects of 4 commonly prescribed drugs-metoprolol, citalopram, oxybutynin, and oxycodone-on LSEC function. We examined their impact on LSEC viability, endocytosis, and fenestration morphology at both systemic steady-state and first-pass concentrations, separately and in a polypharmacy cocktail to model clinical exposure. All treatments induced sublethal metabolic changes, but effects on LSEC functions were drug- and concentration-dependent. Citalopram and oxybutynin caused dose-dependent defenestration, whereas metoprolol and oxycodone produced mild, nondose-dependent effects. Endocytic activity was increased with oxybutynin, metoprolol, oxycodone, and the polypharmacy cocktail, whereas citalopram had no effect. The polypharmacy cocktail triggered synergistic defenestration at first-pass concentrations, but not at steady-state levels. These results highlight the concentration-dependent and combinatorial effects of polypharmacy on LSECs, emphasizing the need to consider endothelial responses in drug safety and pharmacokinetic assessments, particularly in patients exposed to multiple medications. SIGNIFICANCE STATEMENT: Polypharmacy is increasingly common, however, its effects on liver sinusoidal endothelial cells remain poorly understood. Using in vitro models, this study shows that drug combinations can induce sublethal functional and structural alterations in these cells, highlighting endothelial dysfunction as a potential early mechanism contributing to drug-induced liver impairment.

Chiral tertiary alcohols are ubiquitous structural motifs in pharmaceutical agents and bioactive molecules, as well as versatile building blocks in organic synthesis, yet general catalytic enantioselective routes to these compounds remain limited. Direct transition-metal-catalyzed enantioconvergent C-O cross-coupling of racemic tertiary alkyl halides with water would provide an attractive entry to these structures, but this strategy remains largely unexplored because water can deactivate metal catalysts and presents a formidable challenge for enantiocontrol. Herein, we report a copper-catalyzed enantioconvergent O-alkylation of water with racemic α-tertiary haloamides through a radical-polar crossover pathway. Central to this process is the use of chiral anionic N,N,N-ligands, which promote the formation of coordinatively saturated Cu(III) intermediates that undergo enantioselective outer-sphere nucleophilic substitution by water, thereby enabling direct C(sp3)-O bond formation. This method provides practical and complementary access to a broad range of enantioenriched, sterically congested tertiary alcohols under mild conditions with good functional-group compatibility. The synthetic utility of this protocol is further demonstrated by the efficient preparation of diverse chiral tertiary alcohol building blocks and by concise syntheses of pharmaceutically relevant molecules, including sofpironium bromide and (S)-oxybutynin.

Obstructive sleep apnea syndrome (OSAS) is a potentially life-threatening condition that is increasingly prevalent in developed countries. OSAS treatment involves multiple components, including general lifestyle modifications and specific interventions such as intraoral fixation devices and continuous positive airway pressure (CPAP). Surgical treatments, including correction of nasopharyngeal and oropharyngeal structures, orthognathic operations, and bariatric surgery, are used under strict indications. Until recently, pharmacological management was limited to nasal decongestants for rhinitis exacerbation and modafinil for daytime sleepiness. However, low compliance with non-surgical therapies and limited efficacy of some surgical procedures highlight the need for effective drug treatments for OSAS. Despite decades of research, a highly effective pharmacological therapy was not available until the past 6-7 years, when new agents and their combinations were evaluated. Randomization by OSAS endotype is now recognized as crucial in clinical studies. This review summarizes recent advances in OSAS drug therapy, primarily based on randomized clinical trials, with a focus on agents such as semaglutide, tirzepatide, atomoxetine-oxybutynin, solriamfetol, sultiame, and acetazolamide, as well as established drugs. Further research with long-term follow-up and consideration of OSAS endotypes and drug side effects is needed. The importance of combining different therapeutic approaches for OSAS is emphasized.