Donor safety in living donor liver transplantation using the right lobe.
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Hepatectomy↗
Biomedical subjects
I C Kim
Publications and source records attributed to I C Kim.
Endogenous glycosylphosphatidylinositol-specific phospholipase C releases renal dipeptidase from kidney proximal tubules in vitro.
Spontaneous enzymic release of renal dipeptidase (RDPase; EC 3.4.13.19), a glycosylphosphatidylinositol (GPI)-linked ectoenzyme, was observed in vitro during incubation of porcine proximal tubules at 37 degrees C. Triton X-114 phase separation of the released RDPase showed that the majority of the enzyme activity partitioned into the aqueous phase, indicating its hydrophilic nature. Immunoblot analyses using an antibody against the cross-reacting determinant (CRD) inositol 1,2-cyclic monophosphate, the epitope formed by phospholipase C (PLC) cleavage of the GPI anchor on a protein, detected the released RDPase. Reprobing the immunoblot with an anti-RDPase serum showed the RDPase band co-migrating with the CRD band. The release of RDPase from the proximal tubules was a Ca(2+)-dependent process and had a pH optimum of 9.0. These results indicate that RDPase is released from the proximal tubules by the action of a distinct endogenous GPI-specific PLC.
Animals↗
Trigger digits in children.
Seven thousand, seven hundred newborn children were examined prospectively to determine the congenital incidence of trigger thumb and finger. No cases were found. The case histories of 43 trigger digit cases (35 trigger thumbs and eight trigger fingers) noted in 40 children diagnosed at our center between 1995 and 1998 were reviewed with special reference to the spontaneous recovery rate, treatment outcome, and age at presentation. Of the 35 thumb cases, 23 underwent surgical release and all responded satisfactorily to surgical treatment. Spontaneous recovery was noted in 12 trigger thumb cases and in all eight trigger finger cases. Trigger finger developed earlier in life than trigger thumb and the spontaneous recovery rate was higher in trigger finger than trigger thumb.
Child, Preschool↗
Asp41-His48 region of streptokinase is important in binding to a substrate plasminogen.
Streptokinase is a plasminogen activator protein produced by several strains of beta-hemolytic streptococci. Random mutagenesis of streptokinase was carried out for the determination of critical amino acid residues in plasminogen activation. We selected and sequenced 14 streptokinase mutants with no plasminogen activation activity on skim milk-plasminogen overlay plate. Specific activities of the selected streptokinase mutants were determined with chromogenic assay. Eight mutants (V19F, V35E, E85D, L292R, D325P, D341E, I345N, and M369L) resulted in greatly decreased amidolytic activities. However, unexpectedly, six mutants (D41C, S44K, S44P, R45P, H48T, and D220G) showed substantial amidolytic activities comparable to that of wild type. Moreover, five-point mutations were concentrated on the Asp41-His48 region. These data indicate that the Asp41-His48 region in a streptokinase-plasminogen binary complex plays an important role in binding to a substrate plasminogen.
Amidohydrolases↗
The antithrombotic effects of CI-1028, an orally bioavailable direct thrombin inhibitor, in a canine model of venous and arterial thrombosis.
Direct thrombin inhibitors represent a new class of drug that may offer a therapeutic alternative for the treatment and prevention of thrombembolic conditions, especially on the venous side of the systemic circulation. CI-1028 (PD 172524/LB30057) is a potent, highly selective inhibitor of thrombin that is orally bioavailable. The efficacy of this compound has been demonstrated in animal models in which intra-venous administration was used. The objective of this study was to evaluate the efficacy of CI-1028 after oral administration in a canine electrolytic injury model of venous and arterial thrombosis. CI-1028 was administered via oral gavage, and animals received either saline or 10, 15, 20, or 30 mg/kg of drug. Fifteen minutes later, the dogs were anesthetized and a femoral artery and vein were exposed and instrumented to induce electrolytic injury and thrombosis while continuously monitoring blood flow in the vessels. Maximum blood CI-1028 concentrations of 0.88+/-0.27, 1.8+/-0.3, 2.2+/-0.5, and 3.2+/-0.5 microg/mL were generally achieved 15 to 30 minutes after administering the compound in the 10-, 15-, 20-, and 30-mg/kg groups, respectively. Administration of CI-1028 increased the time to occlusion (TTO), the principal efficacy end point, in a dose-dependent manner in both arteries and veins. The TTO in the control group (n=8) averaged 66+/-11 minutes in the arteries and 69+/-6 minutes in the veins. In dogs treated with 10 mg/kg (n=8), the TTO was not significantly different from that of the control group. In the 15-mg/kg group (n=9) TTO averaged 140+/-27 minutes in the arteries (p=not significant) and 125+/-15 minutes (p<0.05) in the veins. In the 20-mg/kg group (n=8), TTO was significantly longer than controls in both types of vessels, averaging 168+/-30 minutes in the arteries (p=0.05) and 155+/-21 minutes (p<0.05) in the veins. Likewise, at 30 mg/kg (n=8) both the arterial (179+/-17 minutes) and venous (188+/-15 minutes) TTO was significantly prolonged compared with controls. Surgical blood loss and template bleeding times tended to increase in a dose-dependent manner but a statistically significant elevation was detected for template bleeding time only at the highest dose. Dramatic changes in thrombin time were detected, consistent with the CI-1028 mechanism of action. Virtually no changes were detected in prothrombin time. Maximum activated partial thromboplastin time (aPTT) and activated clotting time changes were detected approximately 30 minutes after dosing, and they were approximately twofold and fivefold baseline values, respectively, at the highest dose. In conclusion, these results demonstrate that CI-1028 provides dose-dependent antithrombotic efficacy after oral administration in a canine model of venous and arterial thrombosis.
Administration, Oral↗
Pharmacokinetics and tolerability of gemifloxacin (SB-265805) after administration of single oral doses to healthy volunteers.
Gemifloxacin (known as SB-265805 or LB-20304) is a potent, novel fluoroquinolone compound with a broad spectrum of antibacterial activity. The pharmacokinetics and tolerability of oral gemifloxacin were characterized in healthy male volunteers after a single dose of 20, 40, 80, 160, 320, 600, or 800 mg. Multiple serum and urine samples were collected and analyzed for gemifloxacin using high-performance liquid chromatography with fluorescence detection. Safety assessments included vital signs, 12-lead electrocardiogram readings, hematology, clinical chemistry, urinalysis, and adverse-experience monitoring. Gemifloxacin was rapidly absorbed after all doses. Maximum concentrations of gemifloxacin in serum (C(max)) were achieved approximately 1 h after dosing, after which concentrations in serum declined in a biexponential manner. Values of C(max) and the area under the concentration-time curve in serum from 0 h to infinity (serum AUC(0-infinity)) increased linearly with dose. Serum AUC(0-infinity) values (mean +/- standard deviation) were 0.65+/-0.01, 1.28+/-0.22, 2.54+/-0.31, 5.48+/-1.24, 9.82+/-2.70, 24.4+/-7.1, and 31.4+/-7.6 microg. h/ml following 20-, 40-, 80-, 160-, 320-, 600-, and 800-mg doses, respectively. The terminal phase elimination half-life was independent of dose, with an overall mean of 7.4+/-2.0 h. The profiles indicated that the pharmacokinetic profile is suitable for a once-daily dosing regimen. Approximately 25 to 40% of the administered dose was excreted unchanged in the urine, and renal clearance (ca. 150 ml/min) was independent of dose. There were no significant changes in clinical chemistry, hematology, or urinalysis parameters, vital signs, or 12-lead electrocardiogram readings in subjects, irrespective of dose. The results of these studies support the further investigation of once-daily administration of gemifloxacin.
Administration, Oral↗
Benzylamine-based selective and orally bioavailable inhibitors of thrombin.
A series of p-aminomethylphenylalanine derivatives were investigated as novel thrombin inhibitors. This study led to potent inhibitors of thrombin (Ki up to 3.3 nM) that are trypsin-selective, highly orally bioavailable in rats, and highly permeable across Caco-2 cells. The P1 benzylamine binding mode in the thrombin active site was identified by X-ray crystallographic analysis.
Animals↗
High-performance liquid chromatographic determination of a new oral thrombin inhibitor in the blood of rats and dogs.
A reliable reversed-phase high-performance liquid chromatographic method has been developed for the determination of a new oral thrombin inhibitor (compound I) in the blood of rats and dogs. The analyte was deproteinized with a 1.5 volume of methanol and a 0.5 volume of 10% zinc sulfate, and the supernatant was injected into a 5-microm Capcell Pak C18 column (150 x 4.6 mm I.D.). The mobile phase was a mixture of acetonitrile and 0.2% triethylamine of pH 2.3 (31:69, v/v) with a flow-rate of 1.0 ml/min at UV 231 nm. The retention time of compound I was approximately 9.3 min. The calibration curve was linear over the concentration range of 0.05-100 mg/l for rat blood (r2>0.9995, n=6) and dog blood (r2>0.9993, n=6). The limit of quantitation was 0.05 mg/l for both bloods using a 100-microl sample. For the 5 concentrations (0.05, 0.1, 1, 10, and 100 mg/l), the within-day recovery (n=4) and precision (n=4) were 98.1-104.1% and 1.5-6.8% for rat blood and 95.4-105.7% and 1.4-5.3% for dog blood, respectively. The between-day recovery (n=6) and precision (n=6) were 99.8-105.3% and 3.7-12.6% for rat blood and 87.5-107.1% and 2.9-15.3% for dog blood, respectively. The absolute recoveries were 82.4-93.3%. No interferences from endogenous substances were observed. In conclusion, the presented simple, sensitive, and reproducible HPLC method proved and was used successfully for the determination of compound I in the preclinical pharmacokinetics.
Administration, Oral↗
The Leu-3 residue of Serratia marcescens metalloprotease inhibitor is important in inhibitory activity and binding with Serratia marcescens metalloprotease.
Serratia marcescens metalloprotease inhibitor (SmaPI) is a proteinase inhibitor toward Serratia marcescens metalloprotease (SMP). In sequential deletion analysis of the N-terminal region of the SmaPI, SmaPIs starting at Ser-2 and Leu-3 residues, respectively, had nearly a full inhibitory activity toward SMP. However, SmaPI starting at Ala-4 residue showed severely decreased inhibitory activity. Furthermore, kinetic analysis demonstrated that SmaPI starting at the Ala-4 residue had an inhibition constant for SMP approximately fourfold higher than that of wild-type SmaPI. The interactions of Leu-3 with SMP contribute 0.73 kcal mol-1 to the overall stability of the SMP-SmaPI complex (8.44 kcal mol-1). To elucidate the detailed role of the Leu-3 residue in inhibitory activity of SmaPI, several site-directed mutations were introduced. The inhibitory activities of Leu-3 mutants in which the Leu-3 has been converted to Ala, Asp, Gly, Ile, Lys, Phe, or Pro were correlated with the hydrophobicities of substituted amino acids. About 0.3 kcal mol-1 is attributable to the side chain of the Leu-3 residue in the binding with SMP. From these results, it is suggested that (i) in contrast with the Erwinia chrysanthemi inhibitor, Gly-1 and Ser-2 of SmaPI are not critical and (ii) the hydrophobicity of Leu-3 may be important in its inhibitory activity and binding with SMP.
Amino Acid Sequence↗
Streptokinase secretion by Serratia marcescens signaled by the C-terminal 41 amino acid segment of metalloprotease.
In order to investigate the secretion signal of Serratia marcescens metalloprotease (SMP) and examine the ability of the secretion signal to secrete foreign proteins, hybrid genes encoding the passenger-SMP C-terminal segments were constructed. As a passenger protein, streptokinase (SK) deprived of its signal peptide was used. Three kinds of SMP C-terminal segments containing 41, 80, or 220 amino acid residues were fused to the C-terminus of SK as secretion signals. The SK-SMP chimeric proteins containing 41 or 220 amino acid segments of the SMP C-terminus were secreted into the culture medium by the SMP transporter of S. marcescens. This result suggests that cytoplasmic SK is secreted into the external medium by the C-terminal segments of SMP and also shows that the smallest, 41 amino acid segment of the SMP C-terminus functions as a secretion signal of foreign proteins as well as SMP.
Biological Transport↗
Experience of orthotopic liver transplantation in 11 patients with liver cirrhosis from Korea: medical factors affecting outcome.
Orthotopic liver transplantation (OLT) has evolved to become a standard treatment of choice for end-stage liver diseases. The present study was performed to evaluate the peri-operative medical factors affecting transplantation outcome and to determine if patients with type B viral cirrhosis were acceptable for OLT. A total of 11 patients with end-stage cirrhosis, who have received OLT in Kangnam St. Mary's Hospital since May 1993, included 8 HBV-related cases, 1 Hepatitis C Virus (HCV)-related case, and 2 non-B, non-C cases. One-year cumulative survival rate by Kaplan-Meier method was 43.7%. Factors significantly associated with 1-year survival of the recipients during pre-OLT period were performance status and modified Pugh-Child score (p=0.015 and p=0.015, respectively). Among those 4 patients who lived longer than 1 year, 3 of 4 patients with HBsAg-positive had no HBV re-infection with our protocol. These results suggest that, to improve the outcome of OLT in cirrhosis patients, transplantation should be performed in the stage when patients maintain better performance and hepatic functional reserve during the end-stage of liver cirrhosis. In addition, patients with cirrhosis caused by HBV infection may be indicated for OLT, because HBV re-infection is preventable effectively with a high-dose hepatitis B immunoglobulin protocol.
Adolescent↗
High-performance liquid chromatographic assay of a new HIV-1 protease inhibitor, LB71350, in the plasma of dogs.
A reliable reversed-phase high-performance liquid chromatographic method has been developed for the determination of LB71350 in the plasma of dogs. The analyte was deproteinized with 1.5 volumes of methanol and 0.5 volumes of 10% zinc sulfate, and the supernatant was injected into a 5-microm Capcell Pak C18 column (150x4.6 mm I.D.). The mobile phase was a stepwise gradient mixture of acetonitrile and 0.2% triethylamine-HCl with a flow-rate of 1 ml/min and detection at UV 245 nm. The proportion of acetonitrile was kept at 52% for the first 6 min, increased to 100% for the next 0.5 min, kept at 100% for the next 2 min, decreased to 52% for the next 0.5 min, and finally kept at 52% for the next 7 min. The retention time of LB71350 was 6.9 min. The calibration was linear over the concentration range of 0.1-100 mg/l for dog plasma (r>0.997) and the limit of quantitation was 0.1 mg/l using 0.1 ml plasma. The quality control samples were reproducible with acceptable accuracy and precision at 0.1, 1, 10 and 100 mg/l concentrations. The within-day recovery (n=5) was 90.2-93.9%, the between-day recovery (n=5) was 89.5-93.5%, and the absolute between-day recovery (n=5) was 77-81%. The within-day precision (n=5) and between-day precision (n=5) were 2.59-5.82% and 3.17-4.55%, respectively. No interferences from endogenous substances were observed. Taken together, the above HPLC assay method by deproteinization and UV detection was suitable for the determination of LB71350 in the preclinical pharmacokinetics.
Administration, Oral↗
High-performance liquid chromatographic assay of bromocriptine in plasma and eye tissue of the rabbit.
A reliable reversed-phase high-performance liquid chromatographic method has been developed for the determination of bromocriptine (BCT) in plasma and eye tissues. The BCT and propranolol, added as an internal standard (I.S.), were extracted by a liquid-liquid technique followed by an aqueous back-extraction, allowing injection of an aqueous solvent into a 4-microm Nova-Pak C18 column (150x3.9 mm I.D.). The mobile phase was a mixture of 30 parts of acetonitrile and 70 parts of 0.2% triethylamine (pH 3) at a flow-rate of 1 ml/min. Fluorescence detection was at an excitation wavelength of 330 nm and an emission wavelength of 405 nm. The retention times of I.S. and BCT were 4.1 and 11.6 min, respectively. The calibration curve was linear over the concentration range 0.2-10 microg/l for plasma (r>0.999) and vitreous humour (r>0.997) and 1-50 microg/l for aqueous humour (r>0.985). The limit of quantification was 0.2 microg/l for plasma and vitreous humour using a 1-ml sample and was 1 microg/l for aqueous humour using a 0.2-ml sample. The quality control samples were reproducible with acceptable accuracy and precision. The within-day recovery (n=3) was 100-102% for plasma, 91-106% for aqueous humour and 96-111% for vitreous humour. The between-day recovery (n=9) was 90-114% for plasma, 83-115% for aqueous humour and 90-105% for vitreous humour. The within-day precision (n=3) and the between-day precision (n=9) were 1.7-7.0% and 8.1-13.6%, respectively. No interferences from endogenous substances were observed. Taken together, the above simple, sensitive and reproducible high-performance liquid chromatography assay method was suitable for the determination of BCT in plasma and eye tissues following ocular application of BCT for the therapy of myopia.
Animals↗
Identification of the functional importance of valine-19 residue in streptokinase by N-terminal deletion and site-directed mutagenesis.
Streptokinase (SK) is a bacterial plasminogen activator of multi-domain structure. In deletion analysis of the N-terminal region of SK, the deletion of 20 amino acids (SK delta N20) resulted in the dramatic reduction of plasminogen activator activity compared to deletion of 7 (SK delta N7) and 13 amino acids (SK delta N13). The incubation time to reach maximal active site generation in an equimolar mixture of SK delta N20 and plasminogen was the same as that for wild-type SK. To identify the functional residues important in plasminogen activation, several site-directed mutations were introduced at the region spanning Ser16-Val20 of SK. The results showed that Val19 residue is important for the activity of the SK-plasminogen complex.
Amino Acid Sequence↗
Pharmacokinetics of recombinant human erythropoietin in rabbits and 3/4 nephrectomized rats.
The nonlinear pharmacokinetics (1000, 5000, and 10000 IU/kg) and tissue distribution (5000 IU/kg) of erythropoietin (EPO) after intravenous administration of recombinant human EPO (rhuEPO) to rabbits, extent of absolute bioavailability (F) of EPO after subcutaneous administration (5000 IU/kg) to rabbits, and pharmacokinetics of EPO after intravenous administration to 3/4 nephrectomized rats (1000 IU/kg) were investigated. After intravenous administration of rhuEPO, 1000 IU/kg to rabbits, the terminal half-life, t1/2 (296, 368, and 378 min) and mean residence time (255, 318, and 326 min) decreased significantly, however, the total body clearance, CL (0.233, 0.165, and 0.169 ml/min/kg) and nonrenal clearance, CLNR (0.196, 0.141, and 0.120 ml/min/kg) increased significantly when compared with those of 5000 and 10000 IU/kg. The above dose-dependent pharmacokinetic parameters of EPO could be due to saturable metabolism of EPO in rabbits. The affinity of EPO to rabbit tissues studied was very low as reflected to less-than-unity values of tissue to plasma ratios except in the bile. This was supported by a considerably low value of volume of distribution of EPO at steady state (Vss) after intravenous administration of rhuEPO, 1000-10000 IU/kg, to rabbits (0.0524-0.0591 l/kg). After subcutaneous administration of rhuEPO, 5000 IU/kg, to rabbits, the plasma concentration of EPO was reached its peak at 600-720 min and declined slowly with a mean t1/2 of 1040 min. The F value after subcutaneous administration to rabbits was 43.1%. After intravenous administration of rhuEPO, 1000 IU/kg, to control and 3/4 nephrectomized rats, the CL, CLNR, and Vss were not significantly different, however, the MRT and CLR were significantly different between two groups of rats.
Animals↗
RcsC-mediated induction of colanic acid by secretion of streptokinase in Escherichia coli K-12.
The introduction of a plasmid containing skc (streptokinase-coding gene) fused with ompA signal sequence into Escherichia coli K-12 strains, rendered the bacteria mucoid. Measurement of the synthesis of beta-galactosidase from a cps-lacZ fusion (lacZ fusion to a gene necessary for capsule synthesis) showed that the mucoid phenotype was due to induction of the capsular polysaccharide colanic acid synthesis. The introduction of a plasmid carrying skc fused with malE (gene encoding maltose-binding protein) also induced cps-lacZ expression, but intracellular expression of streptokinase in E. coli did not. The cps expression by secretion of streptokinase was diminished to the basal level in a cps-lacZ strain carrying a rcsC mutation. These results show that the secretion of streptokinase in E. coli induces colanic acid synthesis through the RcsC-dependent pathway.
Bacterial Proteins↗
C-terminal peptide of streptokinase, Met369-Pro373, is important in plasminogen activation.
Streptokinase(SK), a plasminogen activator, is known to have multi-domain structure. The function of the C-terminal region of streptokinase was investigated with SK mutants constructed by truncating 26, 33, 37, 40, 41, 46, 47, 70 or 97 amino acid residues from the C-terminus. The truncated SKs were expressed in E. coli and purified. The 41 residue deletion (SKP373) from the C-terminus had not effect on the plasminogen activation activity. However, the deletion of 46 amino acid residues (SKP368) resulted in the dramatic reduction of the plasminogen activation efficiency. The result suggests that the C-terminal peptide from Met369 to Pro373 of SK may play an important role on the plasminogen activation.
Cloning, Molecular↗
In-vitro and in-vivo antibacterial activity of LB10517, a novel catechol-substituted cephalosporin with a broad antibacterial spectrum.
LB10517 is a new injectable cephalosporin with a broad spectrum of antibacterial activity against Gram-positive and Gram-negative bacteria. LB10517 inhibited 90% of methicillin-susceptible Staphylococcus aureus (MSSA) at 0.25 mg/L (MIC90), and was 8-fold more active than cefpirome. LB10517 was two- or four-fold more active than cefpirome against methicillin-susceptible Staphylococcus epidermidis (MSSE), Streptococcus pyogenes and Enterococcus faecalis. Both methicillin-resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis (MRSE) were highly resistant to all compounds. LB10517 activity against most Enterobacteriaceae was comparable to or greater than that of cefpirome, and it also showed high activity against Pseudomonas aeruginosa. In a mouse septicaemia model, LB10517 exhibited excellent protective effects. In a respiratory tract infection model, the protective effect of LB10517 was comparable to that of cefpirome and ceftazidime. It was highly stable to hydrolysis by beta-lactamases, showing better physiological efficiency for TEM-9 than the other test compounds. LB10517 had the most potent antibacterial activity against beta-lactamase producing resistant strains. LB10517 did not induce beta-lactamase production in Enterobacter cloacae 1194E.
Animals↗