Biochemical, pharmaceutical and therapeutic properties of long-acting lithocholic acid derivatized exendin-4 analogs

Chae, S.Y.,Jin, C.H.,Shin, J.H.,Son, S.,Kim, T.H.,Lee, S.,Youn, Y.S.,Byun, Y.,Lee, M.S.,Lee, K.C. Elsevier Science Publishers 2010 Journal of controlled release Vol.142 No.2

Alterations in the physicochemical characteristics of peptide drugs can transform their biological and pharmaceutical features. In the present study, we explored the potentials of lithocholic acid (LCA)-modified exendin-4 derivatives as novel long-acting GLP-1 receptor agonists. Exendin-4 was modified with lithocholic acid at two lysine residues to produce three derivatives that were obtained by reverse-phase HPLC separation, namely, Lys<SUP>12</SUP>-LCA-exendin-4 (LCA-M2), Lys<SUP>27</SUP>-LCA-exendin-4 (LCA-M1), and Lys<SUP>12,27</SUP>-LCA-exendin-4 (LCA-Di)). The biological, pharmacological, and physicochemical characteristics of these three exendin-4 analogues were then investigated. Although slight reductions in the GLP-1 receptor binding capacity and insulinotropic activity of exendin-4 were observed after derivatization, the mono-LCA substitutions, especially LCA-M1, well-preserved antidiabetic activity in type 2 diabetic mice when administered subcutaneously or intraperitoneally. Furthermore, the pharmacokinetic characteristics were dramatically enhanced, that is, absorption was delayed and elimination half-life was increased (1.6+/-0.4 and 9.7+/-1.4h by exendin-4 and LCA-M1, respectively). The enhanced long-acting characteristics of the derivative was found to be due to albumin binding and nanoparticle formation, and these were verified by the restoration of normoglycemia in type 2 diabetic mice after single injection (>24h, >10nmol/kg, s.c.) and daily injections (15nmol/kg/day) maintained normoglycemia for the 4-week administration period. Furthermore, antidiabetic potentials, such as, glucose clearance kinetics and percentage areas occupied by pancreatic β-cells were also enhanced by long-term LCA-M1 administration. The present study demonstrates that the derivatization of exendin-4 with LCA offers a possible means of producing a long-acting GLP-1 receptor agonist.

A novel chimeric promoter that is highly responsive to hypoxia and metals

Lee, J-Y,Lee, Y-S,Kim, J-M,Kim, K L,Lee, J-S,Jang, H-S,Shin, I-S,Suh, W,Jeon, E-S,Byun, J,Kim, D-K Nature Publishing Group 2006 Gene Therapy Vol.13 No.10

To develop a potent hypoxia-inducible promoter, we evaluated the usefulness of chimeric combinations of the (Egr-1)-binding site (EBS) from the Egr-1 gene, the metal-response element (MRE) from the metallothionein gene, and the hypoxia-response element (HRE) from the phosphoglycerate kinase 1 gene. In transient transfection assays, combining three copies of HRE (3 × HRE) with either EBS or MRE significantly increased hypoxia responsiveness. When a three-enhancer combination was tested, the EBS–MRE-3 × HRE (E–M–H) gave a hypoxia induction ratio of 69. The expression induced from E–M–H-pGL3 was 2.4-fold higher than that induced from H-pGL3 and even surpassed the expression from a human cytomegalovirus promoter-driven vector. The high inducibility of E–M–H was confirmed by validation studies in different cells and by expressing other cDNAs. Gel shift assays together with functional overexpression studies suggested that increased levels of hypoxia-inducible factor 1α, metal transcription factor-1 and Egr-1 may be associated with the high inducibility of the E–M–H chimeric promoter. E–M–H was also induced by hypoxia mimetics such as Co<SUP>2+</SUP> and deferoxamine (DFX) and by hydrogen peroxide. Gene expression from the E–M–H was reversible as shown by the reduced expression of the transgene upon removal of inducers such as hypoxia and DFX. In vivo evaluation of the E–M–H in ischemic muscle revealed that erythropoietin secretion and luciferase and LacZ expression were significantly higher in the E–M–H group than in a control or H group. With its high induction capacity and versatile means of modulation, this novel chimeric promoter should find wide application in the treatment of ischemic diseases and cancer.Gene Therapy (2006) 13, 857–868. doi:10.1038/sj.gt.3302728; published online 9 February 2006

복합재료 특성 평가 1 : 다축 구조 S-2 유리섬유 복합재의 충격 특성

송승욱 ( S. W. Song ),이창훈 ( C. H. Lee ),변준형 ( J. H. Byun ),황병선 ( B. S. Hwang ),엄문광 ( M. K. Um ),이상관 ( S. K. Lee ) 한국복합재료학회 2005 한국복합재료학회 학술발표대회 논문집 Vol.- No.1

Cytogenetic profiles of 2806 patients with acute myeloid leukemia—a retrospective multicenter nationwide study

Byun, J. M.,Kim, Y. J.,Yoon, H. J.,Kim, S. Y.,Kim, H. J.,Yoon, J.,Min, Y. H.,Cheong, J. W.,Park, J.,Lee, J. H. Springer Science + Business Media 2016 Annals of hematology Vol.95 No.8

<P>The cytogenetic and molecular data is recognized as the most valuable prognostic factor in acute myeloid leukemia (AML). Our aim was to systemically analyze the cytogenetics of Korean AML patients and to compare the cytogenetic profiles of various races to identify possible geographic heterogeneity. We retrospectively reviewed medical records of 2806 AML patients diagnosed at 11 tertiary teaching hospitals in Korea between January 2007 and December 2011. The most common recurrent chromosomal abnormality was t(8;21) (8.8 %, 238/2717), but t(15;17) showed an almost same number (8.6 %,235/2717). Among de novo AML, the most frequent aberrations were t(15;17), observed in 229 (10.7 %). The most common French-American-British (FAB) classification type was M2 (32.2 %), and recurrent cytogenetic abnormalities correlated with the FAB subtypes. Among 283 secondary AML cases, myelodysplastic syndrome was the most common predisposing factor. About 67.1 % of the secondary AML cases were associated with chromosomal aberrations, and chromosome 7 abnormalities (n = 45, 15.9 %) were most common. The incidence of FLT3 internal tandem duplication mutation was relatively low at 15 %. Our study reports certain similarities and differences in comparison to previous reports. Such discrepancies call for extensive epidemiological studies to clarify the role of genetic as well as geographic heterogeneity in the pathogenesis of AML.</P>

S45C 소재의 금속학적 물성치 획득 및 적용

김성완(S. W. Kim),이라니미쌈(M. Irani),변종복(J. B. Byun),모하마드카스완디라지리(M. K. Razali),전만수(M. S. Joun) 한국소성가공학회 2019 한국소성가공학회 학술대회 논문집 Vol.2019 No.10

간질 환자의 차량 운전

변영주,하정상,박미영 영남대학교 의과대학 1994 Yeungnam University Journal of Medicine Vol.11 No.1

1. 현재 보편적으로 참고가 되는 간질 환자의 운전 면허 허용의 기준과 관련 법규등을 요약하면 표-5와 같다. 2. 아직 어떤 국가에서는 간질환자의 차량운전을 무경련 기간에 상관없이 금하고 있으나, 대다수의 국가에서는 일정한 기간의 무경련의 존재가 면허허용의 중요한 기준으로 삼고 있으며, 대략 1년간의 기간을 요구하고 있다. 그러나 간질은 그 특징상 1년 혹은 2년의 무경련후에도 경련이 발 Table 5. Selected recommendations and standards for driving and seizures ---------------------------------------------------------------------------- Relevant issues Parsonage EFA?? Spudis Doege& et al?? et al Engelberg -------------------------------------------------------------------------- Individualized Support and Support Support Support assessment emphasize strongly -------------------------------------------------------------------------- Sz-free interval 1 to 2 yr Individualized 3m to 1yr 6m to 1yr determinations 2yr without medication ----------------------------------------------------------------------------- Mandatory physician Oppose Oppose Oppose No specific position ------------------------------------------------------------------------------ Mitigating factors Recognize Recommend Many Sleep many short deprivation sz-free and nocturnal sz interval ------------------------------------------------------------------------------- Restricted licenses Temporary Recommend Support No comment licenses strongly ------------------------------------------------------------------------ Commercial driving Individualized Individualized No comment Current evaluations evaluations standards -------------------------------------------------------------------------- Sz:seizure (Parsonage M.1982) EFA:Epilepsy Foundation of America 생될 수 있어 1년간의 무경련으로 면허 발급을 허가는 제도는 더 연구하여 보완할 필요가 있다. 3. 수면시 간질, 전구증상이 있는 복합 부분 간질, 단순 운동성 간질, 특수한 여건이나 자극에서 생기는 경련환자에게 선택적으로 운전면허 허용은 장시간 운전, 고속 운전, 심리적 ·육체적 과로상태에서 운전을 하는 경우 기존 경련을 심하게 유발하거나, 평소와 다른 상황에서 경련이 생길 수 있어 이런 환자들에게 일괄적으로 면허를 허용하기 보다는 세밀하게 분석하여 개인별로 판별하여야 하는 것이 바람직하다. 4. 환자의 능동적이고 성실한 경련보고와 아울러 경련발생 가능성이 높아 의사의 운전중단 처방을 수용하고 따르는 협조적인 환자의 자세가 매우 중요한데, 현재까지 환자의 성실한 경련보고와 의사의 조치에 대한 환자의 적극적인 수용자세가 해결되지 않고 있다.

S25C의 DSA 현상의 정량화 및 응용

이현준(H. J. Lee),M.K. Razali,변종복(J. B. Byun),지수민(S. M. Ji),전만수(M. S. Joun) 한국소성가공학회 2021 한국소성가공학회 학술대회 논문집 Vol.2021 No.5

원발성 간암에서 PIVKA-II 및 Lens Culinaris Agglutinin-A 반응성 Alpha-fetoprotein(AFP-L3)의 임상적 유용성

배시현,박두호,양진모,박영민,차상복,최종영,성광용,조세현,정규원,선희식,김부성,최상욱,변병훈,한남익 대한간학회 2000 Clinical and Molecular Hepatology(대한간학회지) Vol.6 No.2

Background/Aims: Des-γ-carboxy prothrombin(DCP), a protein induced by vitamin K absence or antagonist-II(PIVKA-II), and Lens culinaris agglutinin-A reactive AFP-L3 have been reported to be useful markers for the diagnosis of hepatocellular carcinoma (HCC). In the present study, both the PIVKA-II and AFP-L3 were analyzed and compared with a conventional AFP to determine its usefulness, specificity and sensitivity in the diagnosis of HCC. Methods: Sera were collected from 108 patients consisting of 17 patients with chronic hepatitis, 22 patients with liver cirrhosis and 69 patients with HCC. The AFP-L3 was determined by an lectin affinity electrophoresis coupled with an antibody-affinity blotting. Level of DCP was measured by an enzyme immunoassay with an anti-DCP monoclonal antibody. Results: The sensitivity and specificity of PIVKA-II and AFP L3 were 49.3% and 89.5%, and 32.5% and 85.7%, respectively. No significant correlation was found between the PIVKA-II or AFP L3 and serum AFP. No correlation was found etween the PIVKA-II or AFP L3 and the characteristics of HCC. Conclusion: The determination of plasma DCP and AFP L3 levels combined with AFP levels may be useful especially for the differential diagnosis between HCC and chronic liver diseases without HCC.(Korean J HepatoBackground/Aims: Des-γ-carboxy prothrombin(DCP), a protein induced by vitamin K absence or antagonist-II(PIVKA-II), and Lens culinaris agglutinin-A reactive AFP-L3 have been reported to be useful markers for the diagnosis of hepatocellular carcinoma (HCC). In the present study, both the PIVKA-II and AFP-L3 were analyzed and compared with a conventional AFP to determine its usefulness, specificity and sensitivity in the diagnosis of HCC. Methods: Sera were collected from 108 patients consisting of 17 patients with chronic hepatitis, 22 patients with liver cirrhosis and 69 patients with HCC. The AFP-L3 was determined by an lectin affinity electrophoresis coupled with an antibody-affinity blotting. Level of DCP was measured by an enzyme immunoassay with an anti-DCP monoclonal antibody. Results: The sensitivity and specificity of PIVKA-II and AFP-L3 were 49.3% and 89.5%, and 32.5% and 85.7%, respectively. No significant correlation was found between the PIVKA-II or AFP-L3 and serum AFP. No correlation was found etween the PIVKA-II or AFP L3 and the characteristics of HCC. Conclusion: The determination of plasma DCP and AFP-L3 levels combined with AFP levels may be useful especially for the differential diagnosis between HCC and chronic liver diseases without HCC.(Korean J Hepatol 2000;6:205-214)l 2000;6:205-214)

국내시장에 유통중인 한우 및 수입 쇠고기 냉동 등심 부위의 물리 화학적 미생물학적 및 관능적 품질 특성

이무하,민중석,김일석,변준석,강석남,이상욱 한국축산학회 2000 한국축산학회지 Vol.42 No.1

This study was carried out to compare qualities of the frozen imported beef loins with those of the Han-woo beef loins. Samples were stored at -20℃. In the proximate analysis of composition of beef loins, there were significant differences in crude fat, crude protein and moisture(P$lt;0.001). Han-woo loins were higher in crude protein and moisture than those of the other loins. In the analysis of microorganisms, TPC(Total Plate Counts) and psychrotroph bacterial counts of the Han-woo loins showed the lowest value. TBARS(Thiobarbituric Acid Reactive Substance) values were less than 0.4㎎MA/㎏ in all samples, VBN(Volatile Basic Nitrogen) values were less than 20㎎/100g in all samples. In the descriptive analysis with scaling for raw and cooked beef loins, it was observed that off-flavor of American raw beef loins was higher than that of other ones. In cooked beef loins, acceptability was higher in the Han-woo loins than in the imported ones.

Orally active desulfated low molecular weight heparin and deoxycholic acid conjugate, 6ODS-LHbD, suppresses neovascularization and bone destruction in arthritis

Hwang, S.R.,Seo, D.H.,Al-Hilal, T.A.,Jeon, O.C.,Kang, J.H.,Kim, S.H.,Kim, H.S.,Chang, Y.T.,Kang, Y.M.,Yang, V.C.,Byun, Y. Elsevier Science Publishers 2012 Journal of controlled release Vol.163 No.3

The regulation of angiogenesis is an interesting area to consider for novel therapeutic approaches to rheumatoid arthritis (RA). Chemically modified heparins have been developed as possible candidates for angiogenesis inhibitor; however, they have a major clinical drawback in exhibiting poor oral bioavailability. Here, orally absorbable O-desulfated low molecular weight heparin (ODS-LMWH) derivatives were newly synthesized by conjugating 2-O- or 6-O-desulfated LMWH with deoxycholic acid (DOCA) or bisDOCA (a dimer of DOCA), and their physicochemical properties, antiangiogenic potency and pharmacokinetic profiles were assessed. After selecting the best candidate among those derivatives, its therapeutic efficacy on arthritis was investigated in a murine collagen antibody-induced arthritis (CAIA) model. ODS-LMWH derivatives significantly inhibited the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) and basic fibroblast growth factor (bFGF)-induced angiogenesis in the Matrigel plug assay. Among all the compounds, 6ODS-LHbD showed the highest oral bioavailability in rats (19.3%). In the CAIA mouse model, 6ODS-LHbD (10mg/kg, p.o., S.I.D.) significantly inhibited neovascularization in the joint, the increase of hind-paw thickness, and the structural damage in the bone. Therefore, 6ODS-LHbD would be a promising candidate for an orally active drug for the treatment of RA.