Delirium is an acute neurocognitive impairment triggered by physiological stressors such as medical illness, surgery, or medication use. Although often transient, it is associated with adverse clinical outcomes. Current management primarily relies on nonpharmacological or symptomatic approaches; however, their effectiveness remains limited. Therefore, strategies that target the underlying pathophysiological mechanisms of delirium are of considerable clinical interest. Neuroinflammation has been proposed as a key mechanism in the development of delirium, with inflammatory cytokines produced during systemic inflammation impairing neuronal function. Vitamin D3 (VD3) exerts neuroprotective effects by suppressing the production of inflammatory cytokines. In this study, we hypothesized that VD3 reduces the risk of delirium. To test this hypothesis, a mouse model of postoperative delirium was established using anesthesia and surgery (AS). Cognitive function was assessed using behavioral tests, including the novel object recognition test. Mice subjected to AS exhibited impaired cognitive function, whereas VD3 administration attenuated this impairment. Serum interleukin-6 levels were elevated in the AS group but were reduced following VD3 treatment, consistent with the behavioral findings. These findings suggest that VD3 attenuates cognitive impairment in this postoperative delirium-like mouse model and is associated with reduced serum IL-6 levels. Further studies are required to clarify the underlying mechanisms and the relationship between peripheral and central inflammatory responses.

Long-term l-3,4-dihydroxyphenylalanine (l-DOPA) therapy for Parkinson’s disease increases plasma concentrations of 3-O-methyldopa (3-OMD), a major metabolite of l-DOPA. This study aimed to investigate the role of 3-OMD in the central nervous system (CNS)-mediated behavioral effects associated with chronic l-DOPA treatment in rats. The effects of 3-OMD on CNS function were examined using two rat models: repeated oral co-administration of l-DOPA/benserazide and single or repeated intraperitoneal (i.p.) administration of 3-OMD. Behavioral assessments included spontaneous locomotor activity, spontaneous alternation behavior (SAB), spatial learning, and depression-like behavior. Plasma and brain concentrations of 3-OMD were also measured. Repeated oral administration of l-DOPA/benserazide maintained plasma 3-OMD concentrations at 1.57–3.50 μg/mL and brain concentrations at 1.68–3.23 μg/g. This treatment reduced SAB by up to 30% and showed a trend toward reduced spatial learning, whereas locomotor activity was unaffected. Repeated i.p. administration of 3-OMD produced comparable plasma and brain concentrations of 3-OMD, reduced SAB, and showed a trend toward reduced spatial learning, without affecting other behaviors. The reduction in SAB was reversed after a 7-d washout period. In contrast, a single administration of 3-OMD had no detectable behavioral effects. In conclusion, sustained, but not transient, exposure to 3-OMD may contribute to reduced working memory performance during chronic l-DOPA therapy.

The use of cell-penetrating peptides (CPPs) for the intracellular delivery of pharmaceuticals has progressed from basic research to global clinical studies. In this study, we investigated the effects of introducing l-homoarginine into the CPP oligoarginine on intracellular uptake and membrane permeability efficiency. We demonstrated that extending the arginine side chain by one methylene group (l-homoarginine) significantly increased the intracellular uptake of hexa-oligoarginine compared with extension of the main chain by one carbon atom (l-β-homoarginine). Incorporation of the l-homoarginine sequence improved the short-term stability of hexa-oligoarginine in fetal bovine serum. Furthermore, this strategy showed potential utility in boron neutron capture therapy; when used as an intracellular delivery vehicle, the l-homoarginine-containing peptide facilitated the intracellular delivery of therapeutic boron-containing agents and the effects of thermal neutron irradiation, resulting in increased cancer cell killing. These findings demonstrate that the introduction of l-homoarginine residues is an effective approach for improving the intracellular delivery efficiency and biological stability of CPPs.

Ruxolitinib is a Janus kinase inhibitor effective against graft-versus-host disease and hemophagocytic lymphohistiocytosis. However, clinical management is challenged by potential drug–drug interactions and adverse events. Although therapeutic drug monitoring (TDM) can optimize drug safety and efficacy, real-world pharmacokinetic data are limited. To address this gap, we established a simple and sensitive LC-MS/MS method with a total run time of 8.1 min. The method demonstrated linearity over a range of 0.5–100 ng/mL. The intra- and inter-day precision and accuracy met the acceptance criteria. The method was successfully applied to 8 pediatric and 10 adult patients. Measurable concentrations were confirmed in infants (<2 years). The observed trough concentrations varied widely, ranging from 0.69 to 22.2 ng/mL in pediatric patients and <0.5 to 80.6 ng/mL in adult patients. Notably, an intraindividual comparison in one adult case revealed that posaconazole co-administration increased the trough concentration by approximately 4-fold and the area under the plasma concentration–time curve by approximately 2-fold, compared with the period without azoles. In conclusion, we established a validated LC-MS/MS method that was applicable to the measurement of ruxolitinib concentrations in pediatric and adult patients in this single-center study. This method may contribute to the accumulation of pharmacokinetic data for future evaluation of TDM strategies.