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Ji-Hyun Kang,1,2,&ast; Jin-Hyuk Jeong,1,&ast; Yong-Bin Kwon,1 Young-Jin Kim,1 Dae Hwan Shin,1 Yun-Sang Park,3 Soonsil Hyun,1 Dong-Wook Kim,4 Chun-Woong Park1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2School of Pharmacy, Institute of New Drug Development, and Respiratory Drug Development Research Institute, Jeonbuk National University, Jeonju, Republic of Korea; 3Research & Development Center, P2K Bio, Cheongju, Republic of Korea; 4College of Pharmacy, Wonkwang University, Iksan, 54538, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Chun-Woong Park, College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea, Tel +82-43-261-3330, Fax +82-43-268-2732, Email cwpark@cbnu.ac.kr Dong-Wook Kim, College of Pharmacy, Wonkwang University, Iksan, 54538, Republic of Korea, Tel +82-63-229-7130, Fax +82-63-850-7309, Email pharmengin@gmail.comPurpose: Effective mucosal delivery of drugs continues to pose a significant challenge owing to the formidable barrier presented by the respiratory tract mucus, which efficiently traps and clears foreign particulates. The surface characteristics of micelles dictate their ability to penetrate the respiratory tract mucus. In this study, polymeric micelles loaded with insulin (INS) were modified using mucus-penetrative polymers.Methods: We prepared and compared polyethylene glycol (PEG)-coated micelles with micelles where cell-penetrating peptide (CPP) is conjugated to PEG. Systematic investigations of the physicochemical and aerosolization properties, performance, in vitro release, mucus and cell penetration, lung function, and pharmacokinetics/pharmacodynamics (PK/PD) of polymeric micelles were performed to evaluate their interaction with the respiratory tract.Results: The nano-micelles, with a particle size of < 100 nm, exhibited a sustained-release profile. Interestingly, PEG-coated micelles exhibited higher diffusion and deeper penetration across the mucus layer. In addition, CPP-modified micelles showed enhanced in vitro cell penetration. Finally, in the PK/PD studies, the micellar solution demonstrated higher maximum concentration (Cmax) and AUC0-8h values than subcutaneously administered INS solution, along with a sustained blood glucose-lowering effect that lasted for more than 8 h.Conclusion: This study proposes the use of mucus-penetrating micelle formulations as prospective inhalation nano-carriers capable of efficiently transporting peptides to the respiratory tract.Keywords: insulin, polyethylene glycol, cell-penetrating peptide, aerodynamic properties, mucus penetration

Hye Ran Kim,1 So Yeon Lee,1 Ga Eun You,2 Hye One Kim,1 Chun Wook Park,1 Bo Young Chung1 1Department of Dermatology, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, 07441, Korea; 2Research and Development Institute, Biosolution, Seoul Technopark, Seoul, 01811, KoreaCorrespondence: Bo Young Chung, Department of Dermatology, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, 1 Singil-ro, Yeongdeungpo-gu, Seoul, 07441, Korea, Tel +82-2-829-5221, Fax +82-2-832-3237, Email victoryby@hallym.or.krIntroduction: Exosomes play a key role in cell communication and are involved in both pathological and physiological processes. Autophagy dysfunction and oxidative stress are linked to immune-mediated inflammatory diseases such as psoriasis. Stem cell-derived exosomes exhibit immunomodulatory and antioxidant efficacy.Methods: We aimed to investigate the impact of psoriasis serum-derived exosomes on inflammation, oxidative stress, and autophagy in keratinocytes. Additionally, we explored the therapeutic potential of adipose-derived stem cell (ADSC) exosomes against inflammation induced by psoriasis serum exosomes. To validate psoriasis patient serum-derived exosomes and ADSC exosomes, we used nanoparticle tracking analysis, Western blotting, flow cytometry, and immunofluorescence. qPCR was used to study changes in the gene expression of proinflammatory cytokines and oxidative stress markers in HaCaT cells treated with psoriasis serum-derived exosomes or ADSC exosomes. The effects of these exosomes on autophagy in HaCaT cells were evaluated by Western blotting and immunofluorescence.Result: The treatment of HaCaT cells with psoriasis serum-derived exosomes increased proinflammatory cytokine production and oxidative stress-related factor (Nox2 and Nox4) expression and decreased Nrf2 expression via P65/NF-κB and P38/MAPK activation. Compared with healthy control serum-derived exosomes, psoriasis serum-derived exosomes decreased ATG5, P62, Beclin1, and LC3 expression and autophagosome production in HaCaT cells. Conversely, ADSC exosomes suppressed proinflammatory cytokine and oxidative stress production, and restored autophagy in HaCaT cells treated with psoriasis serum-derived exosomes.Discussion: These findings suggest that ADSC exosomes exhibit a suppressive effect on psoriasis serum exosome-induced inflammation and oxidative stress by regulating autophagy in keratinocytes.Keywords: exosomes, adipose-derived stem cell, psoriasis, autophagy, oxidative stress

Ji-Hyun Kang,1,&ast; Ji-Eun Lee,1,&ast; So-Jeong Jeong,1 Chun-Woong Park,1 Dong-Wook Kim,2 Kwon-Yeon Weon3 1College of Pharmacy, Chungbuk National University, Cheongju, Korea; 2College of Pharmacy, Wonkwang University, Iksan, Korea; 3College of Pharmacy, Daegu Catholic University, Gyeongsan, Korea&ast;These authors contributed equally to this workCorrespondence: Dong-Wook Kim, College of Pharmacy, Wonkwang University, Iksan, 54538, Korea, Tel +82-63-229-7130, Fax +82-63-850-7309, Email pharmengin@gmail.com Kwon-Yeon Weon, College of Pharmacy, Daegu Catholic University, Gyeongsan, 38430, Korea, Tel +82-53-850-3616, Fax +82-53-850-3602, Email weonky@cu.ac.krPurpose: This study aimed to ensure the convenience of administration and reproducibility of efficacy, regardless of the meal, by improving the solubility of rivaroxaban (RIV).Methods: RIV is a non-vitamin K antagonist oral anticoagulants that exhibits a coagulation effect by directly inhibiting coagulation factor Xa. However, RIV has a very low solubility; therefore, it must be administered with a meal at high doses. We used a drug- hydroxypropyl-beta-cyclodextrin (CD)-water-soluble polymer triple complex (R-C-P complex) to solubilize RIV. Using Minitab, we evaluated the effect of each factor on RIV solubility and developed an optimal R-C-P complex formulation. The amount of CD, amount of polymer, and polymer type were set as the independent variables X1, X2, and X3, respectively. RIV solubility (Y1) and dissolution rate for 45 min in pH 4.5 medium (Y2) and pH 1.2 medium (Y3) were set as response variables.Results: The most efficient RIV solubilization effect was obtained from the composition using CD and HPMC 2208, and physicochemical properties and dissolution parameters were analyzed. RIV in the R-C-P complex was present in an amorphous form and showed high solubility. Unlike commercial products, it showed a 100% dissolution rate. The R-C-P complex formulation secured high RIV solubility and 100% release regardless of pH.Conclusion: The results imply that high-dose RIV can be administered regardless of the meal, reducing the risk of changing the drug effect due to the patient’s administration mistake.Keywords: rivaroxaban, drug-cyclodextrin-polymer triple complex, solubilization, design of experiment

Chang-Soo Han,1,&ast; Ji-Hyun Kang,1,&ast; Young-Jin Kim,1 Dong-Wook Kim,2 Chun-Woong Park1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2College of Pharmacy, Wonkwang University, Iksan, 54538, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Chun-Woong Park, College of Pharmacy, Chungbuk National University, 194-21, Osongsangmyeong 1-ro, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea, Tel +82-43-261-3330, Fax +82-43-268-2732, Email cwpark@cbnu.ac.krIntroduction: Dry powder inhalations are an attractive pharmaceutical dosage form. They are environmentally friendly, portable, and physicochemical stable compared to other inhalation forms like pressurized metered-dose inhalers and nebulizers. Sufficient drug deposition of DPIs into the deep lung is required to enhance the therapeutic activity. Nanoscale surface roughness in microparticles could improve aerosolization and aerodynamic performance. This study aimed to prepare microspheres with nanoscale dimples and confirm the effect of roughness on inhalation efficiency.Methods: The dimpled-surface on microspheres (MSs) was achieved by oil in water (O/W) emulsion-solvent evaporation by controlling the stirring rate. The physicochemical properties of MSs were characterized. Also, in vitro aerodynamic performance of MSs was evaluated by particle image velocimetry and computational fluid dynamics.Results: The particle image velocimetry results showed that dimpled-surface MSs had better aerosolization, about 20% decreased X-axial velocity, and a variable angle, which could improve the aerodynamic performance. Furthermore, it was confirmed that the dimpled surface of MSs could cause movement away from the bronchial surface, which helps the MSs travel into the deep lung using computational fluid dynamics.Conclusion: The dimpled-surface MSs showed a higher fine particle fraction value compared to smooth-surface MSs in the Andersen Cascade Impactor, and surface roughness like dimples on microspheres could improve aerosolization and lung deposition.Keywords: nanoscale dimple, aerodynamic performance, particle image velocimetry, computational fluid dynamics

Hye Ran Kim, Hye One Kim, Jin Cheol Kim, Chun Wook Park, Bo Young Chung Department of Dermatology, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, 07441, Republic of KoreaCorrespondence: Bo Young Chung, Department of Dermatology, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, 07441, Republic of Korea, Tel +82-2-829-9092, Fax +82-2-832-3237, Email victoryby777@gmail.comObjective: Psoriasis is a chronic inflammatory skin disorder associated with impairment of epidermal differentiation. Many signaling pathways, including those involved in aryl hydrocarbon receptor (AHR) and autophagy dysfunction, are reportedly associated with the pathogenesis of psoriasis. However, the discrete effects of dioxin via AHR activation or autophagy on the epidermal barrier remain unclear. In the current study, we evaluated the effects of autophagy modulators (chloroquine [CQ] and rapamycin) and the AHR agonist TCDD on the expression of epidermal barrier proteins in psoriasis-like keratinocytes and psoriasis lesional skin tissue culture.Methods: Polycytokine-stimulated human keratinocytes and psoriasis skin biopsies were treated with TCDD, CQ, or rapamycin, and the expression of keratinocyte differentiation-related factors, such as S100A7, S100A8, HRNR, IVL, FLG, and KRT10, was examined by Western blotting or quantitative-polymerase chain reaction.Results: TCDD upregulated S100A7 and S100A8 expression in polycytokine-stimulated HaCaT cells compared to that in unstimulated cells. CQ decreased HRNR, IVL, and KRT10 mRNA levels, while rapamycin increased HRNR, IVL, and KRT10 mRNA levels in HaCaT cells relative to that in unstimulated cells. Co-treatment with CQ reversed TCDD-induced elevation in FLG, HRNR, and IVL mRNA expression. In psoriasis skin tissue, TCDD induced the upregulation of HRNR, IVL, S100A7, and S100A8 compared with that in normal skin. In ex vivo cultures treated with CQ, IVL expression in psoriasis skin tissue was repressed compared to that in normal skin tissue.Conclusion: Our data suggest that autophagy modulation or AHR activation affects processes involved in epidermal differentiation and relates to the pathogenesis of chronic inflammatory skin diseases with skin barrier abnormalities such as psoriasis.Keywords: aryl hydrocarbon receptor, autophagy, keratinocyte differentiation, 2,3,7,8-tetrachlorodibenzo-p-dioxin, chloroquine

Hee Ji Shin,1,&ast; Min Jeong Jo,1,&ast; Ik Sup Jin,1 Chun-Woong Park,1 Jin-Seok Kim,2 Dae Hwan Shin1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2Drug Information Research Institute (DIRI), College of Pharmacy, Sookmyung Women’s University, Seoul, 04310, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Dae Hwan ShinCollege of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, 28160, Republic of KoreaTel +82 43 261 2820Fax +82 43 268 2732Email dshin@chungbuk.ac.krPurpose: We aimed to develop a nanocarrier formulation incorporating fenbendazole (FEN) and rapamycin (RAPA) with strong efficacy against A549 cancer cells. As FEN and RAPA are poorly soluble in water, it is difficult to apply them clinically in vivo. Therefore, we attempted to resolve this problem by encapsulating these drugs in polymeric micelles.Methods: We evaluated drug synergy using the combination index (CI) values of various molar ratios of FEN and RAPA. We formed and tested micelles composed of different polymers. Moreover, we conducted cytotoxicity, stability, release, pharmacokinetic, and biodistribution studies to investigate the antitumor effects of FEN/RAPA-loaded mPEG-b-PCL micelles.Results: We selected mPEG-b-PCL-containing FEN and RAPA at a molar ratio of 1:2 because these particles were consistent in size and had high encapsulation efficiency (EE, %) and drug loading (DL, %) capacity. The in vitro cytotoxicity was assessed for various FEN, RAPA, and combined FEN/RAPA formulations. After long-term exposures, both the solutions and the micelles had similar efficacy against A549 cancer cells. The in vivo pharmacokinetic study revealed that FEN/RAPA-loaded mPEG-b-PCL micelles had a relatively higher area under the plasma concentration–time curve from 0 to 2 h (AUC0– 2 h) and 0 to 8 h (AUC0– 8 h) and plasma concentration at time zero (Co) than that of the FEN/RAPA solution. The in vivo biodistribution assay revealed that the IV injection of FEN/RAPA-loaded mPEG-b-PCL micelles resulted in lower pulmonary FEN concentration than the IV injection of the FEN/RAPA solution.Conclusion: When FEN and RAPA had a 1:2 molar ratio, they showed synergism. Additionally, using data from in vitro cytotoxicity, synergism between a 1:2 molar ratio of FEN and RAPA was observed in the micelle formulation. The FEN/RAPA-loaded mPEG-b-PCL micelle had enhanced bioavailability than the FEN/RAPA solution.Keywords: combination therapy, drug interaction, cytotoxicity, biodistribution, bioavailability

Ji-Hyun Kang*,1 Jinmann Chon*,2 Young-Il Kim,1 Hyo-Jung Lee,1 Dong-Won Oh,1 Hong-Goo Lee,1 Chang-Soo Han,1 Dong-Wook Kim,3 Chun-Woong Park11College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea; 2School of Medicine, Kyung Hee University, Seoul, Republic of Korea; 3Department of Pharmaceutical Engineering, Cheongju University, Cheongju, Republic of Korea*These authors contributed equally to this workBackground: Tacrolimus (TCR), also known as FK-506, is a biopharmaceutics classification system (BCS) class II drug that is insoluble in water because of its high log P values. After dermal application, TCR remains in the stratum corneum and passes through the skin layers with difficulty.Purpose: The objectives of this study were to develop and evaluate solid lipid nanoparticles (SLNs) with thermosensitive properties to improve penetration and retention.Methods: We prepared TCR-loaded thermosensitive solid lipid nanoparticles (TCR-SLNs) with different types of surfactants on the shell of the particle, which conferred the advantages of enhancing skin permeation and distribution. We also characterized them from a physic point of view and performed in vitro and in vivo evaluations.Results: The TCR contained in the prepared TCR-SLN was in an amorphous state and entrapped in the particles with a high loading efficiency. The assessment of ex vivo skin penetration using excised rat dorsal skin showed that the TCR-SLNs penetrated to a deeper layer than the reference product (0.1% Protopic®). In addition, the in vivo skin penetration test demonstrated that TCR-SLNs delivered more drug into deeper skin layers than the reference product. FT-IR images also confirmed drug distribution of TCR-SLNs into deeper layers of the skin.Conclusion: These results revealed the potential application of thermosensitive SLNs for the delivery of difficult-to-permeate, poorly water-soluble drugs into deep skin layers.Keywords: tacrolimus, thermosensitive, solid lipid nanoparticle, FT-IR imaging, atopic dermatitis, dermal delivery

Hong-Goo Lee,*,1 Yun-Sang Park,*,1 Jin-Hyuk Jeong,1 Yong-Bin Kwon,1 Dae Hwan Shin,1 Ju-Young Kim,2 Yun-Seok Rhee,3 Eun-Seok Park,4 Dong-Wook Kim,5 Chun-Woong Park11College of Pharmacy, Chungbuk National University, Cheongju 28160, South Korea; 2College of Pharmacy, Woosuk University, Wanju 55338, South Korea; 3College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, South Korea; 4School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea; 5Department of Pharmaceutical Engineering, Cheongju University, Cheongju 28530, South Korea*These authors contributed equally to this workIntroduction: In this study, a dual release bi-layer tablet containing Fesoterodine fumarate (Fst) 5 mg and Mirabegron (Mrb) 50 mg was prepared to investigate the different release behavior of each drug in bilayer tablet. The bilayer tablet was prepared based on monolayer-tablet formulation of each drug.Methods: The optimized bi-layer tablet showed an in vitro dissolution profile similar to commercial reference tablets Toviaz and Betmiga, based on a satisfactory similarity factor. Drug-release kinetics of each drug in the bilayer tablet were evaluated based on dissolution profiles. Drug-release behavior was evaluated by observing the surface of each layer by scanning electron microscopy and measuring the changes in weight and volume of the tablet during dissolution. Drug transfer between each layer was also investigated by Fourier -transform infrared spectroscopic imaging by observing the cross-section of the bilayer tablet cut vertically during dissolution.Results: The release of Fst was well suited for the Higuchi model, and the release of Mrb was well suited for the Hixson-crowell model. Compared with dissolution rate of each monolayer tablet, that of Fst in the bilayer tablet was slightly reduced (5%), but the dissolution rate of Mrb in bilayer tablet was dramatically decreased (20%). Also, a drug-release study confirmed that polymer swelling was dominant in Fst layer compared with polymer erosion, and degradation was dominant in MRB layer. Fourier-transform infrared imaging and 3-D image reconstruction showed that drug transfer in the bilayer tablet correlates with the results of drug-release behavior.Conclusion: These findings are expected to provide scientific insights in the development of a dual-release bilayer drug-delivery system for Fst and Mrb.Keywords: mirabegron, fesoterodine fumarate, swelling property, erosion property, bilayer tablet, FT-IR imaging

Chun-Woong Park,1 Hyo-Jung Lee,1 Dong-Won Oh,1 Ji-Hyun Kang,1 Chang-Soo Han,1 Dong-Wook Kim21College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea; 2Department of Pharmaceutical Engineering, Cheongju University, Cheongju, Republic of KoreaBackground: Norquetiapine (N-desalkyl quetiapine, NQ) is an active metabolite of quetiapine with stable pharmacokinetic and pharmacological properties. However, its short half-life is a drawback for clinical applications, and long-acting formulations are required. Purpose: The objectives of this study were to prepare improved entrapment efficiency NQ freebase microspheres by the solvent evaporation method with poly(d,l-lactic-co-glycolic acid) (PLGA) as a release modulator and to evaluate their physicochemical and in vitro/in vivo release properties.Methods: NQ freebase PLGA (1:5 w/w) formulations were prepared by the oil-in-water (o/w) emulsion–solvent evaporation method. A solution of the drug and PLGA in 9:1 v/v dichloromethane:ethanol was mixed with 0.2% polyvinyl alcohol and homogenized at 2,800 rpm. The emulsion was stirred for 3 h to dilute and evaporate the solvent. After that, the resulting product was freeze-dried. Drug-loading capacity was measured by the validated RP-HPLC method. The surface morphology of the microspheres was observed by scanning electron microscopy (SEM), and the physicochemical properties were evaluated by differential scanning calorimetry, powder X-ray diffraction, and Fourier-transform infrared spectroscopy particle size distribution. The in vitro dissolution test was performed using a rotary shaking bath at 37°C, with constant shaking at 50 rpm in sink condition. Results: The NQ freebase microspheres prepared by o/w emulsion-solvent evaporation showed over 30 % efficiency. NQ was confirmed to be amorphous in the microspheres by powder X-ray diffraction and differential scanning calorimetry. Special chemical interaction in the microspheres was not observed by FT-IR. The in vitro dissolution test demonstrated that the prepared microspheres' release properties were maintained for more than 20 days. The in vivo test is also confirmed that the particles' long acting of the particle were maintained. Therefore, good in vitro–in vivo correlation was established.Conclusion: In this study, NQ freebase-PLGA microspheres showed potential for the treatment of schizophrenia for long-periods.Keywords: schizophrenia, freebase, o/w emulsion-solvent evaporation, freeze dry, active metabolite, IVIVC

Ju-Young Kim,1,* Sung-Hoon Lee,2,3,* Chun-Woong Park,4 Yun-Seok Rhee,5 Dong-Wook Kim,6 Junsang Park,3 Moonseok Lee,3 Jeong-Woong Seo,2 Eun-Seok Park2 1College of Pharmacy, Woosuk University, Wanju-gun, Republic of Korea; 2School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea; 3GL Pharmtech, Seongnam, Republic of Korea; 4College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea; 5College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea; 6Department of Pharmaceutical Engineering, Cheongju University, Cheongju, Republic of Korea *These authors contributed equally to this work Abstract: The aim of present study was to design oxycodone once-a-day controlled-release (CR) tablets and to perform in vitro/in vivo characterizations. Release profiles to achieve desired plasma concentration versus time curves were established by using simulation software and reported pharmacokinetic parameters of the drug. Hydroxypropyl methylcellulose (HPMC) 100,000 mPa·s was used as a release modifier because the polymer was found to be resistant to changes in conditions of the release study, including rotation speed of paddle and ion strength. The burst release of the drug from the CR tablets could be suppressed by applying an additional HPMC layer as a physical barrier. Finally, the oxycodone once-a-day tablet was comprised of two layers, an inert HPMC layer and a CR layer containing drug and HPMC. Commercial products, either 10 mg bis in die (bid [twice a day]) or once-a-day CR tablets (20 mg) were administered to healthy volunteers, and calculated pharmacokinetic parameters indicated bioequivalence of the two different treatments. The findings of the present study emphasize the potential of oxycodone once-a-day CR tablets for improved patient compliance, safety, and efficacy, which could help researchers to develop new CR dosage forms of oxycodone. Keywords: pharmacokinetics, oral delivery, in vitro–in vivo correlation, double-layer tablet

Several reports have promoted the root-derived Korean red ginseng (KRG; Panax ginseng) as alternative treatment for erectile dysfunction (ED), and ginsenosides are known to be the principal active ingredients of ginseng. Recent studies showed that ginseng berries produce more ginsenosides than KRG; thus, we investigated the ability of the Korean ginseng berry extract GB0710 to relax the penile corpus cavernosum smooth muscle (CCSM) in this study. As a comparative control, the results were compared to those obtained using KRG. In addition, possible mechanisms of action for GB0710 were investigated. While KRG and GB0710 both displayed dose-dependent relaxation effects on precontracted rabbit CCSM in vitro, GB0710 was shown to be more potent than KRG. The GB0710-induced relaxation could be partially reduced by removing the endothelium. In addition, pre-treatment with several nitric oxide (NO) inhibitors significantly inhibited the relaxation of muscle strips. Furthermore, administration of GB0710 increased intracavernosal pressure (ICP) in a rat in vivo model in both a dose- and duration-dependent manner. Intracellular NO production in human microvascular endothelial cells could be induced by GB0710 and inhibited by NG-monomethyl-L-arginine. In conclusion, GB0710 had a greater relaxation effect on rabbit CCSM than did KRG extract, and increased ICP in a rat model in both a dose- and a duration-dependent manner. This relaxing effect might be mediated by NO production. [ABSTRACT FROM AUTHOR]

Acquired Gitelman syndrome (GS) associated with Sjögren syndrome (SS) is rare, and the test to determine the pathophysiological state of acquired GS in patients with primary SS has not been reported previously. A 47-year-old woman with sicca complex presented to our clinic with intermittent muscle cramping and weakness involving both lower extremities over several months. Laboratory findings showed hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria, which met the criteria for GS. Diagnostic evaluation identified primary SS as the cause of the acquired GS. Light microscopic examination of renal tissue from the patient showed mild tubulointerstitial nephritis. Immunohistochemical staining of renal tissue showed the absence of the sodium-chloride cotransporter (NCCT) in the distal convoluted tubules. Incubation of the patient's serum with normal mouse kidney tissue showed a pattern of NCCT in the distal convoluted tubules similar to that of incubation of normal mouse kidney with the rabbit polyclonal anti-NCCT antibody. This is a rare case of acquired GS associated with primary SS, and our findings suggest the presence of circulating autoantibodies to NCCT. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the improvement of allergic dermatitis in chemical allergen-induced mice by Lactobacillus sakei probio 65. L. sakei probio-65 was isolated from kimchi, a traditional Korean fermented food. This strain was resistant to gastric acidity, bile, and several antibiotics and possessed antimicrobial activity against several pathogenic microorganisms. To investigate whether the probiotic activity of L. sakei probio 65 was effective for treating allergic dermatitis, the organism was supplied to mice triggered by allergen (1-chloro-2,4-dinitrobenzene). Mice that received L. sakei probio 65 showed a more rapid recovery compared to control mice, as assessed by visual evaluation of the severity of allergic dermatitis and levels of immunoglobulin (Ig) E and interleukin (IL)-4. L. sakei probio 65 exhibited good probiotic properties in vitro and in mice and was effective in reducing allergen-induced skin inflammation through the regulation of both elevated IgE and IL-4 in sensitized mice. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the benefit of botulinum toxin type A injection into the ankle plantarflexor muscle on sit-to-stand transfer in children with spastic diplegic cerebral palsy. DESIGN: Case-control study. SETTING: Inpatients in a university-affiliated hospital. SUBJECTS: Forty spastic diplegic children aged from 2 to 6 years (18 children with botulinum toxin type A injection into both gastrocnemius muscles as an experimental group and 14 children without injection as a control group). MAIN MEASURES: Sit-to-stand transfer task was evaluated using a motion analyser (Vicon 370 MA with six infrared cameras). The tests were performed twice with a two- week interval. The changes in temporal, kinematic and kinetic parameters were investigated in each group. RESULTS: In the control group there were no significant changes in any of the measured parameters between the tests. In the experimental group, total duration (s) of sit-to-stand transfer was shortened after injection (4.35 +/- 2.49 to 2.89 +/- 1.48, P < 0.05). The maximal angles (degrees) of pelvic and hip joints were reduced (28.88 +/- 5.53 to 26.57 +/- 3.73 and 90.78+8.69 to 87.23 +/- 8.76) and the initial angle of ankle dorsiflexion was increased (4.41 +/- 6.16 to 7.08 +/- 6.09) after injection (P < 0.05). The maximal moments (Nm/kg) of the hip and knee joints (0.44 +/- 0.17 to 0.51 +/- 0.21 and 0.13 +/- 0.05 to 0.18 +/- 0.14) were increased while that of the ankle joint was reduced (0.32 +/- 0.09 to 0.28 +/- 0.10) after injection (P < 0.05). Only the cases with greater reduction of spasticity showed an improvement on kinematic and kinetic parameters. CONCLUSION: Botulinum toxin type A injection into spastic ankle plantarflexors led to better accomplishment of sit-to-stand transfer in children with spastic diplegic cerebral palsy. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor (PPAR)alpha, a member of the ligand-activated nuclear receptor superfamily, plays an important role in lipid metabolism and glucose homeostasis and is highly expressed in the kidney. The present studies were aimed at determining the role of PPARalpha in the pathogenesis of diabetic nephropathy using PPARalpha-knockout mice and cultured murine mesangial cells. Diabetes was induced using a low-dose streptozotocin protocol in 8-week-old male 129 SvJ PPARalpha-knockout and wild-type mice. Diabetic PPARalpha-knockout and wild-type mice developed elevated fasting blood glucose (P < 0.001) and HbA1c levels (P < 0.001). Renal functional and histopathological changes in diabetic and nondiabetic PPARalpha-knockout and wild-type mice were evaluated after 16 weeks of hyperglycemia. PPARalpha immunostaining of the cortical tubules of diabetic wild-type mice was elevated by hyperglycemia. In diabetic PPARalpha-knockout mice, renal disease with accompanying albuminuria, glomerular sclerosis, and mesangial area expansion was more severe than in diabetic wild-type mice (P < 0.05) and was accompanied by increased levels of serum free fatty acids and triglycerides (P < 0.01). Furthermore, they exhibited increased renal immunostaining for type IV collagen and osteopontin, which was associated with increased macrophage infiltration and glomerular apoptosis. There were no significant differences in these indexes of renal disease between nondiabetic PPARalpha-knockout and wild-type mice and diabetic PPARalpha wild-type mice. In vitro studies demonstrated that high glucose levels markedly increased the expression of type IV collagen, transforming growth factor-beta1, and the number of leukocytes adherent to cultured mesangial cells. Adherence of leukocytes was inhibited by the PPARalpha agonist fenofibrate. Taken together, PPARalpha deficiency appears to aggravate the severity of diabetic nephropathy through an increase in extracellular matrix formation, inflammation, and circulating free fatty acid and triglyceride concentrations. PPARalpha agonists may serve as useful therapeutic agents for type 1 diabetic nephropathy. [ABSTRACT FROM AUTHOR]

We examined metoprolol oxidation capacity in 218 unrelated, healthy Korean subjects using the 8 h urinary metabolic ratio (MR) of metoprolol to alpha-hydroxymetoprolol after an oral dose of 100 mg metoprolol tartrate. The results were compared with those from 295 Japanese and 107 mainland Chinese whose metoprolol oxidation capacities were assessed in a similar manner. The frequency of occurrence of poor metabolisers (PMs) was 0.5% (1/218) in the Korean, 0.7% (2/295) in the Japanese and 0% in the Chinese population. However, the respective mean (+/- s.d.) MRs (0.84 +/- 1.14 and 0.87 +/- 0.90) in the Korean and Japanese extensive metabolisers (EMs) were significantly (P less than 0.001) less than that in the Chinese EMs (2.81 +/- 2.35), and the mode of the distribution histogram and the probit plot of data for Chinese EMs were shifted to the right compared with those for Korean and Japanese EMs. The results indicate that Koreans, like Japanese and mainland Chinese, have a much lower frequency of the PM phenotype of debrisoquine/sparteine-type oxidation compared with that reported for Caucasian populations. Chinese EMs appear to have a lower capacity to metabolise metoprolol to alpha-hydroxymetoprolol compared with Korean or Japanese EMs. [ABSTRACT FROM AUTHOR]

With the emphasis on bilateral hearing nowadays, bilateral cochlear implantation has been tried out for bilateral aural rehabilitation. Bilateral sensorineural hearing loss caused by head trauma can get help from cochlear implantation. We present the case of a 44-year-old man with bilateral otic capsule violating temporal bone fractures due to head trauma. The patient demonstrated much improved audiometric and psychoacoustic performance after bilateral cochlear implantation. We believe bilateral cochlear implantation in such patient can be a very effective tool for rehabilitation. [ABSTRACT FROM AUTHOR]

Keywords:antiphospholipid syndrome; papillary muscle rupture; systemic lupus erythematosus [ABSTRACT FROM PUBLISHER]