Current Issue : July-September Volume : 2026 Issue Number : 3 Articles : 5 Articles
Background/Objectives: Fluvoxamine is commonly prescribed for depressive disorders in elderly patients, a population that frequently exhibits variable drug responses and increased susceptibility to adverse effects due to age-related physiological changes. CYP2D6 polymorphisms may further affect fluvoxamine pharmacokinetics in elderly patients, complicating dose optimization for this group. Previous pharmacogenetic studies examining the impact of CYP2D6 phenotype on fluvoxamine treatment outcomes have primarily focused on younger adults, leaving a gap in understanding its effects on the elderly. Methods: The impact of CYP2D6 phenotypes on fluvoxamine exposure in geriatrics was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach incorporating geriatric-specific physiological parameters. Results: The fluvoxamine PBPK model was verified using clinical pharmacokinetic data from younger and older adults, along with phenotype-dependent exposure differences between CYP2D6 poor metabolizers (PMs) and extensive metabolizers (EMs). Simulations showed that steady-state exposure in elderly patients was 1.8-fold higher than those in younger adults, and 2.1-fold higher in CYP2D6 PMs compared with EMs. Based on these simulations, doses of approximately 50 mg/day for PMs, 50–100 mg/day for intermediate metabolizers (IMs), 100 mg/day for EMs, and 150–200 mg/day for ultrarapid metabolizers (UMs) may be appropriate for elderly patients, accompanied by cautious dose escalation and clinical monitoring. Conclusions: These findings suggest that CYP2D6 genotype-guided dosing may be a useful strategy for optimizing fluvoxamine therapy in elderly patients, with the potential to improve treatment outcomes while minimizing the risk of adverse drug reactions in this high-risk population....
Cochlear implants (CIs) are the primary treatment for severe hearing loss. However, despite advances in electrode materials, implantation remains invasive and can cause trauma, inflammation, loss of residual hearing, and vestibular dysfunction. Foreign body reactions may lead to fibrosis, increasing electrode impedance and compromising device performance. To address insertion-related trauma, there is growing interest in developing electrode carriers that deliver drugs locally, such as dexamethasone, which has demonstrated efficacy in both preclinical and clinical settings. This study investigates a novel coating strategy to optimize the perilymphatic concentration–time profile of dexamethasone and compares it to fully loaded silicone rods, in which the drug is incorporated within the silicone matrix. Silicone rods coated with 1.3 μg, 2.6 μg, or 5.2 μg dexamethasone were implanted into the scala tympani of guinea pigs. Drug concentrations were quantified over 84 days using liquid chromatography–mass spectrometry (LC–MS), and sequential sampling assessed distribution along the scala tympani. Coated rods exhibited an initial burst release, followed by a sustained steady-state phase. The 5.2 μg group peaked at 450 ng/ml, decreasing to 50 ng/ml by day 84. The 2.6 μg group showed a similar profile with proportionally lower levels. Sequential sampling at day 42 after implantation revealed that dexamethasone distributed throughout the length of scala tympani, forming a basal-apical gradient. Compared to fully loaded rods, the coated variants achieved comparable peak concentrations with substantially lower total drug amounts and a prolonged burst phase, which may enhance the suppression of the immediate inflammatory response following implantation. The improved pharmacokinetic efficiency likely also indicates a safer drug exposure profile....
Background: Glaucoma requires therapies that extend beyond intraocular pressure (IOP)- lowering strategies, and baicalein (BA) offers dual IOP-lowering and neuroprotective potential. This study evaluated the pharmacokinetics of BA and its major metabolite baicalin (BG) in mouse eyes and serum after intravitreal (IVT) and oral administration to determine whether non-invasive oral dosing can achieve IVT-comparable ocular exposure. Methods: BA was administered via IVT injection (100 μM) or oral gavage (20 and 200 mg/kg) in mice, and concentrations of BA and BG in serum and ocular tissues were quantified using a validated ultra-performance liquid chromatography–mass spectrometry (UHPLC/MS) method. Results: After IVT, ocular BA peaked at 331.56 ± 17.75 ng/g at 5 min and declined to 7.13 ± 0.79 ng/g at 4 h, with minimal systemic exposure. Oral administration achieved comparable or higher peak ocular BA levels (380.43 ± 52.85 ng/g at 15 min for 20 mg/kg; 309.70 ± 24.75 ng/g at 5 min for 200 mg/kg), with markedly higher ocular area under the concentration–time curve (AUC: 2455.48 ± 667.83 h·ng/g for 200 mg/kg and 1224.88 ± 751.13 h·ng/g for 20 mg/kg) versus IVT (247.07 h·ng/g). Serum BA and BG peaked at 5 min after oral dosing, with systemic BG exposure substantially exceeding BA. Conclusions: Non-invasive oral BA dosing achieves ocular concentrations comparable to IVT injection, with significantly greater overall exposure and favorable pharmacokinetic profiles. This study provides the first demonstration in mice that non-invasive oral BA administration can replace invasive IVT delivery, establishing a strong rationale for its clinical development in glaucoma and retinal disease management....
Background/Objectives: Neoagarotetraose (NA4), a marine-derived tetrasaccharide, holds promise as an anti-inflammatory and antioxidant agent; however, its oral bioavailability and systemic exposure mechanisms require elucidation. Methods: This study characterizes the biopharmaceutical profile of NA4 after oral and intravenous administration using a validated near-infrared fluorescence method based on covalent conjugation with Cy7. Results: Following oral gavage (200 mg/kg), NA4-Cy7 was rapidly absorbed (Tmax: 1.0 h; Cmax: 35.6 mg/L), with prolonged systemic exposure (mean residence time: 13.1 h) and an elimination half-life of 8.9 h. Intravenous administration (25 mg/kg) revealed a low volume of distribution at steady state (Vss: 0.0132 L/kg) and a shorter MRT (4.3 h). Tissue distribution at 24 h showed preferential accumulation in the kidney, liver, and lung, with direct visualization of intact NA4 crossing the intestinal epithelium. Conclusions: These findings demonstrate that fluorescently labeled NA4-Cy7 can cross the intestinal epithelial barrier and reach systemic circulation, supporting its potential as an orally active agent with organ-specific targeting properties....
Background: Novel synthetic opioids (NSOs), including a variety of fentanyl analogs (FAs) and emerging non-fentanyl compounds, have increasingly been implicated in overdose fatalities worldwide. Among these, 4-fluorofuranylfentanyl (4F-FUF) is a potent FA with limited in vivo pharmacotoxicological characterization. In this study, we aimed to i. evaluate the pharmacotoxicological effects of 4F-FUF in male and female mice, ii. determine its pharmacokinetic profile in plasma and tissues of both sexes, and iii. correlate behavioral and physiological responses with plasma concentrations. Methods: Female and male mice were injected intraperitoneally with 4F-FUF at an effective dose of 5 mg/kg. Behavioral and physiological responses, including sensorimotor, motor, and respiratory parameters, were assessed at multiple timepoints post-administration. Plasma and tissue samples (brain, heart, liver, spleen, lung, kidney, and stomach) were collected to determine 4F-FUF concentrations and pharmacokinetic parameters. Correlations between plasma levels and behavioral or physiological outcomes were analyzed separately by sex. Results: 4F-FUF impaired the sensorimotor and motor responses in females and males. Moreover, the FA induced persistent antinociception in males with respect to females. The respiratory depression was sudden and more pronounced in male mice. Plasma concentrations of 4F-FUF were higher and persisted longer in males, indicating slower clearance than in females. This drug was highly distributed in the brain and liver tissues of both sexes. Significant correlations were detected in visual placing, vibrissae responses, spontaneous locomotion, and mechanical analgesia in both sexes. Interestingly, the respiratory rate was only significantly correlated with plasma concentrations in females, highlighting potential sex-specific differences in the relationship between drug exposure and physiological effects. Conclusion: The findings demonstrate marked sex-specific differences in the behavioral and physiological changes and pharmacokinetics of 4F-FUF. These results underscore the importance of considering sex-specific differences in assessing the toxicity and risk profiles of novel synthetic opioids....
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