Biomedical subjects

A Kurihara

Publications and source records attributed to A Kurihara.

At least 19 recordsLinked to original sources

PubMed2007

Prediction of pharmacokinetics of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, in humans using animal data.

The pharmacokinetics of CS-023 (RO4908463, formerly R-115685), a novel parenteral carbapenem antibiotic, in humans was successfully predicted using the data collected from mice, rats, rabbits, and dogs; while inclusion of the monkey data led to a significant underestimation of the total plasma clearance (CL). Double logarithmic plots of CL and distribution volume at the steady-state (Vss) vs. body weight in four animal species were linear with high correlation coefficients; and the predicted CL and Vss values in humans agreed well with the observed values after administration of CS-023 by an intravenous drip infusion for 30 min. The plasma concentration-time profile in humans, which was predicted using a bi-exponential equation fitted to a complex Dedrick plot of the animal data, approximated the observed profile. An underestimation of CL caused by including the monkey data in a prediction is quite likely due to the net tubular reabsorption in monkeys, but not at least in rabbits, dogs, and humans.

Animals↗

PubMed2002

Distinctly abnormal brain metabolism in late-onset ornithine transcarbamylase deficiency.

OBJECTIVE: To assess alterations in brain metabolites in patients with late-onset ornithine transcarbamylase deficiency (OTCD). METHODS: Six unrelated, asymptomatic Japanese late-onset OTCD patients were analyzed by proton MRS ((1)HMRS) using a point-resolved spectroscopy technique (repetition and echo times, 5000 and 30 ms). Localized spectra for the centrum semiovale were acquired and absolute metabolite concentrations were calculated using an LCModel. RESULTS: Compared with age-matched controls, N-acetylaspartate and creatine concentrations were normal in all patients. The glutamine (Gln) plus glutamate concentration was increased in four patients, which progressed in proportion to the clinical stage. myo-inositol (mI) could not be detected in five symptomatic patients. A decreased choline (Cho) concentration was detected in two clinically severe patients. (1)HMRS after liver transplantation in one patient revealed the normalization of all metabolites. CONCLUSION: These findings suggest progression of neurochemical events in OTCD, i.e., mI depletion and Gln accumulation followed by Cho depletion, which is reverse of that in hepatic encephalopathy, i.e., Cho depletion followed by mI depletion and Gln accumulation.

Adolescent↗

PubMed2002

Brain N-acetylaspartate is elevated in Pelizaeus-Merzbacher disease with PLP1 duplication.

OBJECTIVE: To assess alterations in brain metabolites of patients with Pelizaeus-Merzbacher disease (PMD) with the proteolipid protein gene 1 (PLP1) duplications using quantitative proton MRS. METHODS: Five unrelated male Japanese patients with PMD with PLP1 duplications were analyzed using automated proton brain examination with the point resolved spectroscopy technique (repetition and echo time of 5,000 and 30 msec). Localized spectra in the posterior portion of the centrum semiovale were acquired, and absolute metabolite concentrations were calculated using the LCModel. RESULTS: Absolute concentrations of N-acetylaspartate (NAA), creatine (Cr), and myoinositol (MI) were increased by 16% (p < 0.01), 43% (p < 0.001), and 31% (p < 0.01) in patients with PMD as compared with age-matched controls. There was no statistical difference in choline concentration. CONCLUSION: The increased concentration of NAA, which could not be detected by previous relative quantitation methods, suggests two possibilities: axonal involvement secondary to dysmyelination, or increased cell population of oligodendrocyte progenitors. Elevated Cr and MI concentrations may reflect the reactive astrocytic gliosis. Our study thus emphasizes the importance of absolute quantitation of metabolites to investigate the disease mechanism of the dysmyelinating disorders of the CNS.

Aspartic Acid↗

PubMed2001

Adverse effect of dentine bonding agent on the oral mucosa of guinea pigs.

The purpose of present study was to determine the possibility of nebulous discoloration of the oral mucosa of guinea pigs as a result of the application of dentine bonding agents. The materials used were the Clearfil Photo Bond (CPB) system's mixture agent, universal agent and catalyst agent. Four types of experimental catalysts were used. In male albino guinea pigs weighing 300-500 g, oral mucosa irritation tests were performed in accordance with the guidelines of the Cosmetic, Toiletry and Fragrance Association (CTFA). Macroscopical findings on the oral mucosa showed that there was strong nebulous discoloration immediately after application of CPB mix and CPB catalyst and throughout the experimental periods. However, CPB without 10-methacryloxdecyl dihydrogen phosphate (MDP) did not produce noticeable nebulous discoloration and inflammation. The CPB mix caused pathological changes, such as paraketosis and hyperkeratosis on the endepidermis of the mucosa, immediately after its application.

Animals↗

PubMed2001

Investigation of usefulness of sperm analyses in dogs for male fertility study.

The usefulness of sperm analyses in dogs, including sperm motion analysis, was investigated. Sperm motion analysis was performed with the CellSoft-4000 computer-assisted sperm analysis (CASA) system. First, we examined the conditions for preservation of optimal semen quality. We found that sperm retained more of their motility at 4 degrees C than at 37 degrees C. Secondly, we observed sperm motion, concentration and morphology in dog semen continuously for 11 weeks. We collected semen samples during the test period, and the samples retained sperm motion, concentration and morphology. Finally, we administrated alpha-chlorohydrin, which decreases rodent sperm motion, at a single oral dose of 100 mg/kg or 150 mg/kg to dogs. Sperm motion was inhibited immediately after alpha-chlorohydrin treatment, and recovered after 2 weeks. None of the experimental animals were sacrificed in the above-mentioned examinations. We thus confirmed that sperm analyses including motion analysis in dogs are useful in male fertility studies.

Animals↗

PubMed2001

[Four cases of reversible posterior leukoencephalopathy syndrome].

We reported four children cases with reversible posterior leukoencephalopathy syndrome (RPLS). Magnetic resonance imaging (MRI) of the brain demonstrated reversible multiple cortical and subcortical lesions predominant in the occipital region. All patients presented with neurological symptoms associated with hypertension, such as headache, seizures and visual disturbances, which were successfully treated with antihypertensive therapy. Although RPLS is rare in childhood, characteristic lesions on MRI in the hypertensive children should be recognized as manifestations of RPLS. Subsequent clinical management should focus on the treatment of the hypertension and/or its underlying causes.

Adolescent↗

PubMed2001

[Percutaneous cryosurgery for liver tumors].

A new cryoprobe developed in our department makes it possible to perform percutaneous cryoablation for small liver tumors. This cryoprobe is placed into each lesion using an ultrasonic guidance technique. In this study there were 10 patients with hepatocellular carcinoma and 5 patients with liver metastases from colorectal carcinoma. In 6 cases the tumor size was below 2 cm, in 6 cases between 2 and 3 cm, and in 3 cases over 3 cm. Using a cryoprobe of 3 mm in diameter, each lesion was frozen using liquid nitrogen for 15 or 20 minutes then thawed for 10 minutes, and repeated. The ice ball was found to enlarge to 3 cm in 20 minutes and 5 cm in 60 minutes experimentally. Six cases were CR, 5 PR, 2 NC and 2 PD. After cryoablation, liver function did not change and there were no complications. However, as the size of the ice ball was small (about 3 cm), this method was insufficiently effective in some cases. Percutaneous cryoablation using this probe should be performed for tumors smaller than 3 cm.

Aged↗

PubMed2000

Minimum 10-year outcome of decompressive laminectomy for degenerative lumbar spinal stenosis.

STUDY DESIGN: A retrospective follow-up study was conducted in patients who underwent decompressive laminectomy for degenerative lumbar spinal stenosis. OBJECTIVES: To describe the long-term outcome of decompressive laminectomy performed for degenerative lumbar spinal stenosis, and to investigate preoperative factors that influenced outcomes, especially risk factors predisposing patients to poor results. SUMMARY OF BACKGROUND DATA: The success rate of surgical treatment of decompressive laminectomy for lumbar spinal stenosis varies. Long-term follow-up investigations have indicated deterioration of outcome; however, the causes of deterioration have not been fully investigated, and there have been no reports with a minimum 10-year follow-up. METHODS: Of 151 patients who underwent decompressive laminectomy from 1980 through 1989, 37 were followed up for a minimum of 10 years. The mean age at surgery was 60.9 +/- 8. 2 years (range, 43-76), and the average follow-up period was 13.1 +/- 2.1 years (range, 10.1-17.4). The results were evaluated by the criteria of the Japanese Orthopedic Association Lumbar Score, and the outcome was classified as excellent at more than 75% improved score; good, 50-75%; fair, 25-49%; and poor, 0-24% or less. Information about impairment of activities of daily living was also obtained at follow-up. Associations between preoperative clinical and radiographic variables and clinical outcome were evaluated statistically. RESULTS: In all patients, the average score improvement of 55.2 +/- 31.6% was regarded as acceptable. The postoperative score and percentage of improvement of low back pain were lower than those of leg pain and walking ability. No impairment in activities of daily living was found in 62.2% of the patients. Rate of improvement was evaluated as excellent in 13 (35.1%), good in 8 (21.6%), fair in 8, and poor in 8 patients. Three patients required additional surgery because of disc herniation at the laminectomied segments. The patients with multiple laminectomy (P = 0.034) and more than 10 degrees preoperative sagittal rotation angle (P = 0.018) showed a significantly poorer outcome than the remainder of the patients. CONCLUSIONS: Long-term follow-up showed that even without spinal fusion, more than half the patients were evaluated as excellent or good. Patients with more than a 10 degrees sagittalrotation angle who need multiple laminectomy, should be given information about the possibility of earlier deterioration of the outcome, and alternative or additional treatment such as concomitant spinal fusion with decompression may be considered.

Activities of Daily Living↗

PubMed2000

Transport across the primate blood-brain barrier of a genetically engineered chimeric monoclonal antibody to the human insulin receptor.

PURPOSE: Brain drug targeting may be achieved by conjugating drugs, that normally do not cross the blood-brain barrier (BBB), to brain drug delivery vectors. The murine 83-14 MAb to the human insulin receptor (HIR) is a potential brain drug targeting vector that could be used in humans, if this MAb was genetically engineered to form a chimeric antibody. where most of the immunogenic murine sequences are replaced by human antibody sequence. METHODS: The present studies describe the production of the gene for the chimeric HIRMAb, expression and characterization of the protein, radiolabeling of the chimeric HIRMAb with 111-indium and 125-iodine, and quantitative autoradiography of living primate brain taken 2 hours after intravenous administration of the [111In]chimeric HIRMAb. RESULTS: The chimeric HIRMAb had identical affinity to the target antigen as the murine HIRMAb based on Western blotting and immunoradiometric assay using partially purified HIR affinity purified from serum free conditioned media produced by a CHO cell line secreting soluble HIR. The [125I]chimeric HIRMAb was avidly bound to isolated human brain capillaries, and this binding was blocked by the murine HIRMAb. The [111In]chimeric HIRMAb was administered intravenously to an anesthetized Rhesus monkey, and the 2 hour brain scan showed robust uptake of the chimeric antibody by the living primate brain. CONCLUSIONS: A genetically engineered chimeric HIRMAb has been produced, and the chimeric antibody has identical reactivity to the human and primate BBB HIR as the original murine antibody. This chimeric HIRMAb may be used in humans for drug targeting through the BBB of neurodiagnostic or neurotherapeutic drugs that normally do not cross the BBB.

Animals↗

PubMed2000

In vitro metabolism of human and salmon calcitonins in rat liver and kidney evaluated by liquid chromatography-tandem mass spectrometry.

1. Using LC-MS and LC-MS/MS, an in vitro study was conducted on the metabolism of human calcitonin (hCT) and salmon calcitonin (sCT) in rat liver and kidney to determine the rates of metabolism and the positions of hydrolytic cleavage in both peptides. 2. In lysosomal fractions of rat liver and kidney, hCT was degraded 9-12 times faster than sCT. Many metabolites of hCT were produced in the lysosomal fractions, whereas the metabolites of sCT were scarcely found. 3. In the case of the cytosolic fractions, three positions of initial endoproteolytic cleavage were found in hCT, leading to the production of many peptide fragments via subsequent exoproteolytic metabolism. The initial cleavage position of sCT could not be identified precisely, but it was postulated that the rate-determining step in the metabolism of sCT is the endoproteolytic hydrolysis. 4. The studies using pure proteases and protease inhibitors indicated that the metabolism of calcitonins proceeds by initial endoproteolytic cleavage and subsequent exoproteolytic digestion, catalysed by an aspartate-protease in lysosomes and by a metalloprotease and cysteine-protease in combination in the cytosol. 5. The result suggested that the higher in vivo pharmacological activity of sCT compared with that of hCT may be due to a slower metabolism of the former.

Amino Acid Sequence↗

PubMed1999

Imaging brain tumors by targeting peptide radiopharmaceuticals through the blood-brain barrier.

Present day imaging of brain tumors requires a disrupted blood-brain barrier (BBB). However, the BBB is intact in the early stages of brain tumor growth, when diagnosis is most critical. Relative to normal brain, brain tumor cells frequently overexpress peptide receptors, such as the receptor for epidermal growth factor (EGF). Peptide radiopharmaceuticals such as radiolabeled EGF could be used to image early brain tumors, should these radiopharmaceuticals be made transportable through the BBB. The present studies describe a bifunctional molecule that contains both biologically active human EGF radiolabeled with 111In and an anti-transferrin receptor monoclonal antibody that undergoes transcytosis through the BBB via the endogenous transferrin transport system. The two domains of the bifunctional conjugate are separated by a Mr 3400 polyethyleneglycol linker, which releases steric hindrance and allows the conjugate to bind to both the EGF receptor, to image the brain tumor, and to the transferrin receptor, to enable transport through the BBB. Successful imaging of experimental brain tumors with this system is demonstrated in nude rats bearing cerebral implants of human U87 glioma.

Animals↗

PubMed1999

The procedure of polymerase chain reaction-restriction fragment-single strand conformation polymorphism analysis by Hha I/Hinc II to detect mitochondrial DNA mutations.

We reported 56 mitochondrial DNA (mtDNA) mutations in Japanese compared with the Cambridge Sequence by polymerase chain reaction-restriction fragment-single strand conformation polymorphism (PCR-RF-SSCP) analysis. Here we report the principle and the detailed procedures of PCR-RF-SSCP analysis. Restriction map of the 15,673 bp PCR product of mtDNA was designed by MacMolly Tetra, and Hha I and Hinc II were selected. Restriction fragment length polymorphism (RFLP) analysis of 15,673 bp PCR products by Hha I/Hinc II revealed one common pattern and 10 polymorphic patterns compared with the prediction based on the Cambridge Sequence. When the samples were electrophoresed by SSCP analysis, DNA fragments of 912 bp, 772 bp, 761 bp, 634 bp, 431 bp, 327 bp, 226 bp and 171 bp showed 6, 4, 5, 4, 5, 7, 2 and 3 polymorphic patterns, respectively. The determinations of nucleotide sequence of these 46 polymorphic patterns revealed 56 mutations compared with the Cambridge Sequence and 7 of these mutations were common in Japanese. Among these, 20 mutations have not been reported before.

DNA, Mitochondrial↗

PubMed1998

The adverse effect of commercial dentine-bonding systems on the skin of guinea pigs.

It was widely known that 2-hydroxyethyl methacrylate (2-HEMA) can cause contact dermatitis. Commercially available dentine primers and dentine bonding agents that contain 2-HEMA are widely used. The purpose of this study was to investigate the cumulative irritation and delayed hypersensitivity caused by commercial dentine bonding systems when applied to the skin of guinea pigs. We have concluded that almost no dentine bonding systems cause cumulative irritation, but some commercially available dentine bonding systems may produce delayed hypersensitivity.

Animals↗

PubMed1998

Species variation in pharmacokinetics and opsonization of palmitoyl rhizoxin (RS-1541) incorporated in lipid emulsions.

Highly lipophilic antitumor agent, palmitoyl rhizoxin (RS-1541), was incorporated into stable lipid emulsions about 100-1000nm in mean diameter consisting of triglyceride ODO and surfactant HCO-60. The pharmacokinetics of RS-1541 were studied after i.v. injection in mice, rats, rabbits, and dogs. Dog showed characteristic pharmacokinetics of RS-1541, compared with other species. RS-1541 was much more rapidly eliminated from plasma with emulsion particles in dogs than in mice, rats, and rabbits. Most amounts of injected RS-1541 were recovered in the liver six hours after administration to dogs, while less than 20% recoveries were observed for mice and rats. To clarify this species variation, opsonization of emulsion particles were evaluated. When emulsions (about 200nm in size) were opsonized by dog plasma, and intravenously injected to rats, total clearance and liver uptake of RS-1541 were increased to 1.8 fold and 2.7 fold of control values, respectively. In contrasts, emulsions opsonized by mouse, rabbit and human plasma did not show such drastic changes in pharmacokinetics of RS-1541 in rats. Furthermore, total clearance of RS-1541 for emulsions opsonized by dog plasma was increased to 1.9 fold of controls after injection to rabbits. These results indicate that opsonizing activities of dog plasma for RS-1541 emulsions are high, compared with other species. This species variation in opsonizing process probably caused the species variation in the pharmacokinetics of RS-1541 incorporated in lipid emulsions.

Animals↗

PubMed1997

Effects of sematilide, a novel class III antiarrhythmic agent, on membrane currents in rabbit atrial myocytes.

The effects of sematilide, a novel class III antiarrhythmic agent, on membrane currents were examined in single myocytes isolated from the rabbit left atrium, using the whole-cell voltage clamp technique. Application of 10, 30, 100 and 300 microM sematilide caused a concentration-dependent inhibition of the delayed rectifier K+ current (IC50 approx. 25 microM). The sematilide-sensitive current, which was recorded by means of a triangular voltage command, showed a strong inward rectification and had a peak at about -40 mV, suggesting that sematilide inhibits the rapidly activating delayed rectifier K+ current. The Ca2+-independent transient K+ and the inward rectifier K+ currents were not affected significantly by application of 100 microM sematilide. Moreover, voltage-dependent Na+ and Ca2+ currents were not affected significantly by 100 microM sematilide. These findings indicate that sematilide selectively blocks the rapidly activating delayed rectifier K+ current in atrial myocytes and provide evidence supporting the usefulness of the drug as a class III antiarrhythmic agent.

Action Potentials↗

PubMed1996

Lipid emulsions of palmitoylrhizoxin: effects of composition on lipolysis and biodistribution.

Four types of lipid emulsion for highly lipophilic antitumour agent RS-1541 (13-O-palmitoylrhizoxin) with mean particle diameters of 200-260 nm were prepared using soybean oil (SOY) or dioctanoyldecanoylglycerol (ODO) for the oil phase and lecithin (LEC) or polyoxyethylene-(60)-hydrogenated castor oil (HCO-60) for surfactants. The lipolysis rate of HCO-60-emulsified emulsions by lipoprotein lipase was much slower than that of LEC-emulsified emulsions. Particle sizes of emulsions incubated in plasma with the lipase for six hours were 75%, 79%, 101%, and 93% of initial values for SOY/LEC, ODO/LEC, SOY/HCO-60, and ODO/HCO-60 emulsions, respectively, showing an apparent size decrease for LEC-emulsified emulsions. In rats, uptake clearance values of SOY/LEC and ODO/LEC emulsions of RS-1541 in the reticuloendothelial system (RES) were 81.2 and 135.3 mL h(-1), respectively, and AUC values were 4.0 and 1.3 microg h mL(-1), respectively. In contrast, RES uptake clearances of HCO-60 emulsions of RS-1541 were considerably lower (4.2 mL h(-1) for SOY/HCO-60; 2.2 mL h(-1) for ODO/HCO-60), resulting in high AUC values (35.4 microg h mL(-1) for SOY/ HCO-60; 63.9 microg h mL(-1) for ODO/HCO-60). The concentrations of RS-1541 in tumour tissues after an intravenous administration of ODO/HCO-60 emulsions of RS-1541 to mice bearing solid tumour M5076 sarcoma were about ten times higher than those after the administration of SOY/LEC emulsions. These results indicate that HCO-60 emulsions, compared with conventional LEC emulsions, are more stable to lipoprotein lipase and show low uptakes by RES organs, long circulations in the plasma, and high distributions in tumours. Thus, these sterically stabilized emulsions could show potential as effective carriers for highly lipophilic antitumour agents to enhance the drug delivery in tumours.

Animals↗

PubMed1996

Lipid emulsions of palmitoylrhizoxin: effects of particle size on blood dispositions of emulsion lipid and incorporated compound in rats.

Emulsion formulations of various particle sizes for the highly lipophilic antitumour agent, RS-1541 (13-O-palmitoylrhizoxin), were prepared using dioctanoyldecanoylglycerol (ODO) as lipids and polyoxyethylene-(60)-hydrogenated castor oil (HCO-60) as a surfactant. These emulsions were evaluated as injectable drug carriers and compared with a colloidal solution. Both in vitro and in vivo after i.v. administration, RS-1541 was distributed into lipoproteins from the colloidal solution. When applied as emulsions of various particle sizes (124-419 nm) in vitro, RS-1541 was retained and stabilized within the emulsions. In the in vivo study, however, retention of RS-1541 in the emulsions after i.v. injection depended on their size. The small-particle emulsions (94-112 nm) resulted in long retention, and the large-particle emulsions (415-474 nm) led to short retention. Lipolysis rates of emulsion particles by lipoprotein lipase also depended on their size, indicating rapid lipolysis for small-particle emulsions (133 nm). However, the lipolysis was not such an extensive one, showing 10-30% release of capric acid from ODO within 6 h. Blood dispositions of capric acids approximately paralleled those of RS-1541 after i.v. injection of various particle size emulsions (130-368 nm) to rats, although relatively rapid eliminations of capric acids compared with RS-1541 were observed for the small-particle size emulsions (130 nm). These results suggest that when injected as emulsion formulations, the highly lipophilic antitumour agent, RS-1541, has behaviour similar to that of the emulsion particles in the body, which is dependent on the size of the latter. Thus, by properly selecting the particle size, lipid emulsions consisting of ODO and HCO-60 are expected to be effective and useful DDS carriers for RS-1541.

Animals↗

PubMed1996

Enhanced tumor delivery and antitumor activity of palmitoyl rhizoxin using stable lipid emulsions in mice.

PURPOSE: A highly lipophilic antitumor agent, 13-O-palmitoyl-rhizoxin (RS-1541), was incorporated into lipid emulsions of various sizes consisting of triglyceride ODO and surfactant HCO-60. Pharmacokinetics, toxicities, and antitumor activities were evaluated after intravenous administration to mice bearing subcutaneously inoculated M5076 sarcoma cells. METHODS: The levels of RS-1541 in the plasma and tissues including tumor, were determined by HPLC. The maximum tolerated dose (MTD) was estimated by toxic death and change in body weight. The decrease in tumor diameter was measured for antitumor activity. RESULTS: There existed large variations in pharmacokinetics of RS-1541, depending on the size of emulsion particles. Compared with a colloidal solution (reference solution), the small (110nm) and medium (230nm) size emulsions showed high concentrations of RS-1541 in the tumor, while the large emulsions (350nm-630nm) exhibited low concentrations. The MTD of RS-1541 was reduced, when incorporated in the emulsions larger than 220nm in size. At MTD, each size of emulsions (70nm-380nm) effectively retarded the tumor growth and increased survival time. The maximum effect was achieved for the 220 nm emulsions. CONCLUSIONS: When particle size is properly selected, these emulsions could be promising and effective as an injectable carrier for lipophilic antitumor agents in order to enhance the tumor delivery and efficacies while reducing toxicities.

Animals↗