Quantitative Analysis of the Effect of Stereotactic Radiosurgery for Postoperative Residual Cervical Dumbbell Tumors: A Multicenter Retrospective Cohort Study.

OBJECTIVE: Stereotactic radiosurgery (SRS) has been performed for spinal tumors. However, the quantitative effect of SRS on postoperative residual cervical dumbbell tumors remains unknown. This study aimed to quantitatively evaluate the efficacy of SRS for treating postoperative residual cervical dumbbell tumors. METHODS: We retrospectively reviewed cases of postoperative residual cervical dumbbell tumors from 1995 to 2020 in 2 tertiary institutions. Residual tumors underwent SRS (SRS group) or were observed with clinical and magnetic resonance imaging (MRI) follow-up (observation group). Tumor regrowth rates were compared between the SRS and observation groups. Additionally, risk factors for tumor regrowth were analyzed. RESULTS: A total of 28 cervical dumbbell tumors were incompletely resected. Eight patients were in the SRS group, and 20 in the observation group. The mean regrowth rate was not significantly lower (p = 0.784) in the SRS group (0.18 ± 0.29 mm/mo) than in the observation group (0.33 ± 0.40 mm/mo). In the multivariable Cox regression analysis, SRS was not a significant variable (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.18-1.79; p = 0.336). CONCLUSION: SRS did not significantly decrease the tumor regrowth rate in our study. We believe that achieving maximal resection during the initial operation is more important than postoperative adjuvant SRS.

Soccer Ball-like Assembly of Edge-to-edge Oriented 2D-silica Nanosheets: A Promising Catalyst Support for High-Temperature Reforming.

Controlled assembly of nanoparticles into well-defined assembled architectures through precise manipulation of spatial arrangement and interactions allows the development of advanced mesoscale materials with tailored structures, hierarchical functionalities, and enhanced properties. Despite remarkable advancements, the controlled assembly of highly anisotropic 2Dnanosheets is significantly challenging, primarily due to the limited availability of selective edge-to-edge connectivity compared to the abundant large faces. Innovative strategies are needed to unlock the full potential of 2D-nanomaterialsin self-assembled structures with distinct and desirable properties. This research unveils the discovery of controlled self-assembly of 2D-silica nanosheets (2D-SiNSs) into hollow micron-sized soccer ball-like shells (SA-SiMS). The assembly is driven by the physical flexibility of the 2D-SiNSs and the differential electricdouble-layer charge gradient creating electrostatic bias on the edge and face regions. The resulting SA-SiMS structures exhibit high mechanical stability, even at high-temperatures, and exhibit excellent performance as catalyst support in the dry reforming of methane. The SA-SiMS structures facilitate improved mass transport, leading to enhanced reaction rates, while the thin silica shell prevents sintering of small catalyst nanocrystals, thereby preventing coke formation. This discovery sheds light on the controllable self-assembly of 2D nanomaterials and provides insights into the design and synthesis of advanced mesoscale materials with tailored properties.

Unilateral Pediculectomy and Reduction with Short-Segment Pedicle Screw Fixation for Thoracolumbar Burst Fracture: A Case Series.

BACKGROUND: This study aimed to evaluate the efficacy of unilateral pediculectomy and reduction with short-segment pedicle screw fixation for thoracolumbar burst fracture. METHODS: We retrospectively reviewed patients who underwent a unilateral pediculectomy and reduction with short-segment fixation and interbody fusion for thoracolumbar burst fracture. The unilateral pediculectomy created sufficient space to approach the ventral side of the spinal cord for removing bone fragments and insertion of an interbody cage to correct kyphosis. Lumbar lordosis (LL), pelvic incidence (PI) minus LL, and segmental Cobb angle were measured at 3 time points: preoperatively, postoperatively, and final follow-up. Furthermore, sagittal vertical axis (SVA) was measured to assess global sagittal balance at the final follow-up. RESULTS: A total of 10 patients, with a mean age of 39.8 ± 21.0, underwent the surgical procedure. All patients had a thoracolumbar injury classification and severity score > 5. The mean follow-up period was 15.8 ± 13.9 months. The mean postoperative LL (46.0 ± 5.8) was significantly higher (P = 0.008) than the preoperative measurement (32.8 ± 8.2). The mean postoperative PI minus LL (2.2 ± 8.4) was not significantly lower (P = 0.051) than preoperative measurement (15.4 ± 12.6). The mean postoperative segmental Cobb angle (11.4 ± 8.4) was significantly higher (P < 0.001) than the preoperative measurement (-11.6 ± 10.9). At the final follow-up, the mean sagittal vertical axiswas 10.0 ± 28.8 mm. CONCLUSIONS: Unilateral pediculectomy and reduction with short-segment fixation and interbody fusion served as an efficient surgical method for thoracolumbar burst fracture.

Sculpting In-plane Fractal Porous Patterns in Two-Dimensional MOF Nanocrystals for Photoelectrocatalytic CO2 Reduction.

Herein, by choosing few-nm-thin two-dimensional (2D) nanocrystals of MOF-5 containing in-planner square lattices as a modular platform, a crystal lattice-guided wet-chemical etching has been rationally accomplished. As a result, two attractive pore patterns carrying Euclidean curvatures; precisely, plus(+)-shaped and fractal-patterned pores via ⟨100⟩ and ⟨110⟩ directional etching, respectively, are regulated in contrast to habitually formed spherical-shaped random etches on MOF surface. In agreement with the theoretical calculations, a diffusion-limited etching process has been optimized to devise high-yield of size-tunable fractal-pores on the MOF surface that tenders for a compatibly high payload of catalytic ReI -complexes using the existing large edge area once modified into a free amine-group-exposed inner pore surface. Finally, on benefiting from the long-range fractal opening in 2D MOF support structure, while loaded on an electrode surface, a facilitated cross-interface charge-transportation and well-exposure of immobilized ReI -catalysts are anticipated, thus realizing enhanced activity and stability of the supported catalyst in photoelectrochemical CO2 -to-CO reduction.

Management of Cerebrospinal Fluid Leakage by Pump-Regulated Volumetric Continuous Lumbar Drainage Following Anterior Cervical Decompression and Fusion for Ossification of the Posterior Longitudinal Ligament.

OBJECTIVE: Cerebrospinal fluid (CSF) leakage is a major concern related to anterior cervical decompression and fusion for ossification of the posterior longitudinal ligament (OPLL). We propose a management algorithm for CSF leakage following anterior cervical decompression and fusion for OPLL involving the use of pump-regulated volumetric continuous lumbar drainage. METHODS: We retrospectively reviewed patients who underwent anterior cervical decompression and fusion for OPLL and were managed with the proposed algorithm between March 2018 and July 2022. The proposed management algorithm for CSF leakage by pump-regulated volumetric continuous lumbar drainage was as follows. On exposure of the arachnoid membrane with or without CSF leakage, a dural sealant patch was applied to manage the dural defect. In case of persistent CSF leakage despite application of the dural sealant patch, patients underwent pump-regulated volumetric continuous lumbar drainage. RESULTS: Fifty-one patients were included in the study. CSF leakage occurred in 14 patients. Of these 14 patients, 9 patients underwent lumbar drain insertion according to the proposed management algorithm. Successful resolution of CSF leakage was observed in 8 of the 9 patients who underwent lumbar drainage. All patients were encouraged to ambulate without concern of CSF overdrainage due to gravity, because it could be avoided with pump-regulated volumetric continuous CSF drainage. Therefore, complications associated with absolute bed rest or CSF overdrainage were not observed. CONCLUSION: The proposed management algorithm with pump-regulated volumetric continuous lumbar drainage showed safety and efficacy for management of CSF leakage following anterior decompression and fusion for OPLL.

Clinical Features and Prognosis of Diffuse Midline Glioma: A Series of 24 Cases.

BACKGROUND: Diffuse midline glioma (DMG) which occurs in midline structures and characterized by harboring K27M mutation in genes encoding the histone 3 protein is classified as World Health Organization (WHO) grade IV regardless of histological findings and has a poor prognosis. Nevertheless, because of its relatively rare incidence compared with other high-grade gliomas, a comprehensive description encompassing clinical features and genomic profiles of DMG is still lacking. METHODS: In this study, we analyzed data of 24 patients who were diagnosed as DMG which was confirmed by surgical specimens in both pediatric and adult patients. We described the clinical outcomes of patients with DMG and their genomic profiles through a retrospective analysis of 24 patients with DMG. RESULTS: The clinical characteristics of the 24 patients with DMG were analyzed. Ten patients (41%) underwent tumor resection and 14 patients (59%) underwent tumor biopsy. The median overall survival was 10.4 months (95% confidence interval [CI], 8.4 to 12.5) and progression free survival was 3.9 months (95% CI, 2.6 to 5.2). Fifteen patients (62%) were accompanied by hydrocephalus. None of the patient, tumor, or treatment factors had any significant associated with survival. In both immunohistochemistry staining (n=24) and targeted next generation sequencing (n=15), TP53 mutation was the most common genetic mutation (25% and 46%, respectively) found in the patients except alterations in histone 3 protein. CONCLUSION: Although surgical treatment of patient with DMG does not affect the overall survival prognosis, it can help improve the patient's accompanying neurological symptoms in some limited cases. Hydrocephalus is often accompanied with DMG and treatment for hydrocephalus is often also required. Multidisciplinary therapeutic approach is needed.

Crystal Facet-Manipulated 2D Pt Nanodendrites to Achieve an Intimate Heterointerface for Hydrogen Evolution Reactions.

Despite the Pt-catalyzed alkaline hydrogen evolution reaction (HER) progressing via oxophilic metal-hydroxide surface hybridization, maximizing Pt reactivity alongside operational stability is still unsatisfactory due to the lack of well-designed and optimized interface structures. Producing atomically flat two-dimensional Pt nanodendrites (2D-PtNDs) through our 2D nanospace-confined synthesis strategy, this study tackles the insufficient interfacial contact effect during HER catalysis by realizing an area-maximized and firmly bound lateral heterointerface with NiFe-layered double hydroxide (LDH). The well-oriented {110} crystal surface exposure of Pt promotes electronic interplay that bestows strong LDH binding. The charge-relocated interfacial bond in 2D-PtND/LDH accelerates the hydrogen generation steps and achieves nearly the highest reported Pt mass activity enhancement (∼11.2 times greater than 20 wt % Pt/C) and significantly improved long-term operational stability. This work uncovers the importance of the shape and facet of Pt to create heterointerfaces that provide catalytic synergy for efficient hydrogen production.

Anti-inflammatory effects of DA-9601, an extract of Artemisia asiatica, on aceclofenac-induced acute enteritis.

DA-9601 is an extract obtained from Artemisia asiatica, which has been reported to have anti-inflammatory effects on gastrointestinal lesions; however, its possible anti-inflammatory effects on the small intestine have not been studied yet. Therefore, in this study, we investigated the protective effects of DA-9601 against the ACF-induced small intestinal inflammation. Inflammation of the small intestine was confirmed by histological studies and the changes in the CD4+ T cell fraction induced by the inflammation-related cytokines, and the inflammatory reactions were analyzed. Multifocal discrete small necrotic ulcers with intervening normal mucosa were frequently observed after treatment with ACF. The expression of IL-6 , IL-17, and TNF-α genes was increased in the ACF group; however, it was found to have been significantly decreased in the DA-9601 treated group. In addition, DA-9601 significantly decreased the levels of proinflammatory mediators such as IL-1ß, GMCSF, IFN-γ, and TNF-α; the anti-inflammatory cytokine IL-10, on the other hand, was observed to have increased. It is known that inflammatory mediators related to T cell imbalance and dysfunction continuously activate the inflammatory response, causing chronic tissue damage. The fractions of IFN-γ+ Th1 cells, IL-4+ Th2 cells, IL-9+ Th9 cells, IL-17+ Th17 cells, and Foxp3+ Treg cells were significantly decreased upon DA-9601 treatment. These data suggest that the inflammatory response induced by ACF is reduced by DA-9601 via lowering of the expression of genes encoding the inflammatory cytokines and the concentration of inflammatory mediators. Furthermore, DA-9601 inhibited the acute inflammatory response mediated by T cells, resulting in an improvement in ACF-induced enteritis.

Optimization of bilayer tablet manufacturing process for fixed dose combination of sustained release high-dose drug and immediate release low-dose drug based on quality by design (QbD).

A fixed dose combination (FDC) bilayer tablet, consisting of high-dose metformin HCl in a sustained release layer and low-dose evogliptin tartrate in an immediate release layer, was developed based on a quality by design (QbD) approach. To implement QbD approach, the bilayer tableting process parameters judged as high risk through risk analysis were optimized by a central composite face-centered design as a design of experiment (DOE) methodology. Using DOE, the optimized conditions of the tableting process for drug products that satisfy the established quality target product profiles were obtained. The content uniformity of low-dose evogliptin tartrate in the optimized bilayer tablet prepared on a large scale was confirmed by at-line transmittance Raman spectroscopy as a process analytical technology. In addition, the in vitro drug release and in vivo pharmacokinetic studies showed that metformin HCl and evogliptin tartrate in the bilayer tablet is bioequivalent to those of the respective reference drugs. Furthermore, the physicochemical stability of the optimized bilayer tablet during storage under long-term and accelerated conditions was also confirmed. Therefore, it can be concluded that the QbD approach is an effective way to develop a new FDC bilayer tablet that is easy to scale up for successful commercialization.

Silica-Enveloped 2D-Sheet-to-Nanocrystals Conversion for Resilient Catalytic Dry Reforming of Methane.

Here, lamellar confinement strategy is introduced for "sheet-to-nanocrystals (NCs)" conversion within a 2D-SiO2 envelope, which constructs a catalytic nanocartridge holding a platoon of isolated and in-plane-aligned ultrasmall Ni-NCs, performing as a robust and coking-resistant catalytic system for dry reforming of methane. Overcoming the problem of unavoidable bulk crystal growth from multiple sheets-stack or sheet-on-open-support, silica bilayer-encasing tightly clamps the atomic-thin Ni(OH)2 -nanosheet during thermal conversion and further hinders the migratory fusion of the resultant Ni-NCs. Upon heating-cooling cycle, the flapping silica envelope clutches the Ni-NCs like "eggs in a carton," subsequently, ensuring their thermal stability. Owing to the unique 2D-enveloped rigid architecture, Ni-NCs can circumvent sintering and coke deposition while tolerating the high temperatures (>700 °C) for long operation (>100 h), affording high conversions to syngas.

Effect of Penetration Enhancers on Toenail Delivery of Efinaconazole from Hydroalcoholic Preparations.

The incorporation of permeation enhancers in topical preparations has been recognized as a simple and valuable approach to improve the penetration of antifungal agents into toenails. In this study, to improve the toenail delivery of efinaconazole (EFN), a triazole derivative for onychomycosis treatment, topical solutions containing different penetration enhancers were designed, and the permeation profiles were evaluated using bovine hoof models. In an in vitro permeation study in a Franz diffusion cell, hydroalcoholic solutions (HSs) containing lipophilic enhancers, particularly prepared with propylene glycol dicaprylocaprate (Labrafac PG), had 41% higher penetration than the HS base. Moreover, the combination of hydroxypropyl-ß-cyclodextrin with Labrafac PG further facilitated the penetration of EFN across the hoof membrane. In addition, this novel topical solution prepared with both lipophilic and hydrophilic enhancers was physicochemically stable, with no drug degradation under ambient conditions (25 °C, for 10 months). Therefore, this HS system can be a promising tool for enhancing the toenail permeability and therapeutic efficacy of EFN.

Pharmacological evaluation and safety of a donepezil patch.

Our aim was to assess the feasibility of transdermal delivery of donepezil and evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of donepezil patch in vitro and in vivo. Donepezil patches were applied to the skin of rabbits and humans for 7 days, then, the PK profiles were observed in a dose-dependent manner. Donepezil was continuously released from the patch for 7 days as compared to oral administration in hairless rats and rabbits. In hairless rats, peak acetylcholinesterase (AChE) inhibition of 34.7±2.0% was observed within 8 h after oral administration of 4 mg/head donepezil, and lasted for less than 24 h, consistent with changes in the plasma donepezil concentration. Peak AChE inhibition by the donepezil patch was equivalent to that in the orally administered group. Donepezil was released continuously from the patch for 7 days with a linear PK in both rats and rabbits. AChE activity inhibition was dependent on donepezil plasma concentration. The data exhibited excellent PK/PD correlation. There was no dermal irritation (erythema/edema) in placebo or donepezil patch group during the study period in minipigs. Thus, Dong-A's donepezil patch appeared to be generally safe and was well tolerated.

Holey Pt Nanosheets on NiFe-Hydroxide Laminates: Synergistically Enhanced Electrocatalytic 2D Interface toward Hydrogen Evolution Reaction.

Next-generation electrocatalysts with smart integrated designs, maximizing the chemical cascade synergy for sustainable hydrogen production, are needed to address the urgent environmental threats, but scalable synthesis of precisely architectured nanohybrids rendering a few-nanometer interfacial controllability to augment the catalytic reactivity and operational stability is a major bottleneck. Herein, by inventing a surface-confined lateral growth of nanometer-thin and nanoporous two-dimensional (2D)-Pt on NiFe-LDH nanosheets, a highly reactive 2D-2D interfacially integrated nanoplatform is synthesized for an alkaline hydrogen evolution reaction (HER) which not only extracts high Pt-atomic utilization efficiency but also synergistically accelerates the water dissociation and hydrogen generation cascade on the colocalized Pt/M(OH)x active sites, endowing a 6.1-fold higher Pt mass activity than 20% Pt/C and also empowers a record-high HER operational stability for 50 h, due to the chemically enforced lamellar architecture. This work offers a gateway to produce active metal nanosheets tailored with a suitable active-template surface in order to invent and enforce futuristic catalysis technologies.

Preparation, Characterization, and In Vivo Pharmacokinetic Evaluation of Polyvinyl Alcohol and Polyvinyl Pyrrolidone Blended Hydrogels for Transdermal Delivery of Donepezil HCl.

Transdermal delivery systems are emerging platforms for the delivery of donepezil hydrochloride (DH) for treating Alzheimer's disease. The primary aim of this study was to develop polyvinyl alcohol and polyvinyl pyrrolidone blended hydrogels and to evaluate their feasibility for delivering DH via a transdermal route. Physicochemical properties, such as gel fraction (%), swelling ratio (%), weight loss (%), mechanical strength, elongation at break, and Young's modulus of the prepared hydrogels were evaluated. Furthermore, in vitro skin permeation and in vivo pharmacokinetic studies were performed. With an increased concentration of propylene glycol (PG), the gel fraction (%), maximum strength, and elongation at break decreased. However, the swelling ratio (%) and weight loss (%) of hydrogels increased with increased PG content. The 26% PG-hydrogel was superior, with an enhancement ratio of 12.9 (*** p < 0.001). In addition, the 11% PG-hydrogel and 1% PG-hydrogel exhibited an enhancement ratio 6.30-fold (*** p < 0.001) and 2.85-fold (* p < 0.05) higher than that exhibited by control, respectively, indicating a promising effect of PG on skin permeation. In addition, in vivo pharmacokinetic studies on hairless rats assessed the expediency for transdermal delivery of DH. The transdermal delivery of optimized hydrogel-patches with two different doses of DH revealed that the maximum plasma concentration and area under the curve were dose dependent, and the time to reach the maximum concentration was 8 h. Thus, optimized hydrogels have the potential to enhance the transdermal delivery of DH and could be a novel clinical approach.

Effect of Formulation Factors and Oxygen Levels on the Stability of Aqueous Injectable Solution Containing Pemetrexed.

The aim of this study was to investigate the effects of various parameters at each control strategy in drug product degradation on the stability of pemetrexed in injectable aqueous solution. A forced degradation study confirmed that oxidation is the main mechanism responsible for the degradation of pemetrexed in aqueous solutions. As control strategies, the antioxidant levels, drug concentration, pH of the control formulation, dissolved oxygen (DO) levels in the control process, and headspace oxygen levels in the control packaging were varied, and their effects on the stability of pemetrexed were evaluated. Sodium sulfite was found to be particularly effective in preventing the color change, and N-acetylcysteine (NAC) had a significant effect in preventing chemical degradation. The sulfite and NAC were found to stabilize pemetrexed in the aqueous solution by acting as sacrificial reductants. A pH below 6 caused significant degradation. The stability of pemetrexed in the solution increased as the concentration of the drug increased from 12.5 to 50 mg/mL. In addition, the DO levels in the solution were controlled by nitrogen purging, and the oxygen levels in headspace were controlled by nitrogen headspace, which also had significant positive effects in improving the stability of the pemetrexed solution; thus, it was confirmed that molecular oxygen is involved in the rate-limiting oxidation step. Based on these results obtained by observing the effects of various control strategies, the optimal formulation of an injectable solution of pemetrexed is suggested as follows: sodium sulfite at 0.06 mg/mL, as an antioxidant for prevention of color change; NAC at 1.63 mg/mL, as an antioxidant for prevention of chemical degradation; pH range 7-8; DO levels below 1 ppm; and headspace oxygen levels below 1%. In conclusion, it can be suggested that this study, which includes well-designed control strategies, can lead to a better understanding of the complex degradation mechanism of pemetrexed; thus, it can lead to the development of an injectable solution formulation of pemetrexed, with improved stability.

Highly Mesoporous Metal-Organic Frameworks as Synergistic Multimodal Catalytic Platforms for Divergent Cascade Reactions.

Rational engineering and assimilation of diverse chemo- and biocatalytic functionalities in a single nanostructure is highly desired for efficient multistep chemical reactions but has so far remained elusive. Here, we design and synthesize multimodal catalytic nanoreactors (MCNRs) based on a mesoporous metal-organic framework (MOF). The MCNRs consist of customizable metal nanocrystals and stably anchored enzymes in the mesopores, as well as coordinatively unsaturated cationic metal MOF nodes, all within a single nanoreactor space. The highly intimate and diverse catalytic mesoporous microenvironments and facile accessibility to the active site in the MCNR enables the cooperative and synergistic participation from different chemo- and biocatalytic components. This was shown by one-pot multistep cascade reactions involving a heterogeneous catalytic nitroaldol reaction followed by a [Pd/lipase]-catalyzed chemoenzymatic dynamic kinetic resolution to yield optically pure (>99 % ee) nitroalcohol derivatives in quantitative yields.

Design and in vivo evaluation of entecavir-3-palmitate microcrystals for subcutaneous sustained delivery.

The objectives of this study were to formulate microcrystals of entecavir-3-palmiate (EV-P), a palmitic acid ester of entecavir (EV), and evaluate the influence of particle size on its pharmacokinetic behavior following subcutaneous (SC) injection. Systemic toxicity and local tolerability of the hepatitis B anti-viral suspension were further evaluated in normal rats. EV-P microcrystals possessing median diameters of 2.1, 6.3, and 12.7 µm were fabricated using anti-solvent crystallization technique with polysorbate 20 and polyethylene glycol 4000 as steric stabilizer. Dissolution rate of EV-P microcrystals was controlled by adjusting the particle size, under sink condition. Pharmacokinetic profiles of 2.1 µm-sized and 6.3 µm-sized EV-P microcrystals were quite comparable (1.44 mg/kg as EV), over 46 days in rats. The absorption rate and extent of EV after SC injection of 12.7 µm-sized microcrystals were significantly retarded, due to its slower dissolution rate in aqueous media. No single-dose systemic toxicity was observed after SC injection of high dose of EV-P microcrystal suspension (30-300 mg/kg as EV). The microcrystals were tolerable in the injected site, showing mild inflammatory responses at a dose of 30 mg/kg. Therefore, the novel microcrystal system with median particle size of below 6.3 µm is expected to be a unique long-acting system of the anti-viral agent, improving patient's compliance with chronic disease.

Microsuspension of fatty acid esters of entecavir for parenteral sustained delivery.

Entecavir (EV), an anti-viral agent for hepatitis B infection, should be administered under fasted state, as intestinal absorption of this hydrophilic compound is markedly decreased under post-prandial conditions. Herein, in order to improve therapeutic adherence, a parenteral sustained delivery system was constructed, by synthesizing water-insoluble ester prodrugs of the nucleotide analogous with fatty acids. EV-3-palmitate (named EV-P), exhibited the lowest solubility in phosphate buffered saline (pH 7.4, 1.1 µg/ml), with extended release profile compared with EV, EV-3-myristate, and EV-3-stearate, was selected as a candidate to formulate drug suspension. The crystalline suspension was fabricated using anti-solvent crystallization technique, with a mean particle size of 7.7 µm. After subcutaneous (SC) injection in beagle dogs (0.43 mg/kg as EV), the plasma concentrations of EV were markedly protracted with lowered maximum plasma concentration (Cmax, 4.7 ng/ml), extended time required to reach Cmax (Tmax, 9.0 days), and lengthened elimination half-life (T1/2, 129.3 h) compared with those after oral administration (0.0154 mg/kg, Cmax, 15.4 ng/ml; Tmax, 0.01 days; T1/2, 4.1 h). The systemic exposure of the lipidic prodrug was below 0.1% compared with that of EV following SC injection, denoting that EV-P was rapidly converted into the parent compound in blood. Therefore, SC delivery of EV-P microsuspension can be an alternative to oral EV therapy, offering prolonged pharmacokinetic profile after single injection.

The Effects of Donepezil, an Acetylcholinesterase Inhibitor, on Impaired Learning and Memory in Rodents.

A previous study in humans demonstrated the sustained inhibitory effects of donepezil on acetylcholinesterase (AChE) activity; however, the effective concentration of donepezil in humans and animals is unclear. This study aimed to characterize the effective concentration of donepezil on AChE inhibition and impaired learning and memory in rodents. A pharmacokinetic study of donepezil showed a mean peak plasma concentration of donepezil after oral treatment (3 and 10 mg/kg) of approximately 1.2 ± 0.4 h and 1.4 ± 0.5 h, respectively; absolute bioavailability was calculated as 3.6%. Further, AChE activity was inhibited by increasing plasma concentrations of donepezil, and a maximum inhibition of 31.5 ± 5.7% was observed after donepezil treatment in hairless rats. Plasma AChE activity was negatively correlated with plasma donepezil concentration. The pharmacological effects of donepezil are dependent upon its concentration and AChE activity; therefore, we assessed the effects of donepezil on learning and memory using a Y-maze in mice. Donepezil treatment (3 mg/kg) significantly prevented the progression of scopolamine-induced memory impairment in mice. As the concentration of donepezil in the brain increased, the recovery of spontaneous alternations also improved; maximal improvement was observed at 46.5 ± 3.5 ng/g in the brain. In conclusion, our findings suggest that the AChE inhibitory activity and pharmacological effects of donepezil can be predicted by the concentration of donepezil. Further, 46.5 ± 3.5 ng/g donepezil is an efficacious target concentration in the brain for treating learning and memory impairment in rodents.

In vivo gastric residence and gastroprotective effect of floating gastroretentive tablet of DA-9601, an extract of Artemisia asiatica, in beagle dogs.

OBJECTIVE: DA-9601, an extract of Artemisia asiatica containing eupatilin and jaceosidin as active compounds, has been prescribed to treat gastritis in Asia. In recent times, sustained-release, floating gastroretentive (GR) tablets of DA-9601 are available on the market. In the present study, the physical properties and in vitro drug release profile, in vivo gastric residence time, and gastroprotective effect of GR tablet were compared to those of immediate release (IR) tablets of DA-9601. METHOD: In vitro buoyancy behavior (floating lag time and duration) and release profile of eupatilin were assessed in acidic medium. The in vivo intragastric behaviors of the barium sulfate-loaded IR and GR tablets were evaluated in beagle dogs by radiographic studies. Local gastroprotective effect was compared in an experimentally induced gastric lesion in beagle dogs after oral administration of IR (three times per day) or GR (twice daily) tablets for 15 days. RESULTS: Upon contact with gastric juice, a low-density floating tablet (apparent density of 0.93 g/cm(3)) was buoyant on the medium and was upheld for 14 hours, providing sustained drug release profile, whereas the IR tablet disintegrated within 10 minutes, showing complete drug release within 2 hours. In vivo radiographic studies showed that the GR tablet was retained for >4 hours in the stomach. Both DA-9601 formulations remarkably alleviated gastric mucosal injury compared to placebo group, when observed by gastric endoscopy. CONCLUSION: Twice-daily GR tablets exhibited a prolonged gastric residence time and a remarkable mucosal restoration effect in animal models. Therefore, the GR system of DA-9601 could be a substitute dosage form for the treatment of gastritis, while reducing the dosing frequency and thus improving patient compliance.