Biomedical subjects

Kazuko Kobayashi

Publications and source records attributed to Kazuko Kobayashi.

22 records · Page 2Linked to original sources

PubMed2002

Comparative toxicological assessment of a water-soluble azole administered both orally and by intravenous continuous infusion in cynomolgus monkeys.

The water-soluble azole, 4-[1-[(3-methylaminoacetoxymethyl-pyridin-2-yl)-methyl-carbamoyloxy]- ethyl]-1-[(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2- (2,5-difluoro-phenyl)-2-hydroxy-butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride (hereinafter referred to as WSA), is a new water-soluble triazole anti-fungal compound. WSA is rapidly converted into its active metabolite after administration by either the intravenous or oral route. The clinical effects of WSA are expected to be consistent whether it is administered by injection (intravenous) or orally. To evaluate and compare the toxicities of WSA via oral and intravenous administration, repeated toxicity studies of WSA were conducted in cynomolgus monkeys (oral dosage levels: 0, 10, 30 and 90 mg/kg/day over a 4-week period; intravenous infusion dosage levels: 0, 10, 30 and 60 mg/kg/day over a 2-week period). In addition, a 2-week oral toxicity study of the active metabolite of WSA was conducted with similar dosages (0, 10, 30 and 90 mg/kg/day). From the results obtained from the evaluation, hepatotoxicity (liver) and endocrinological toxicity (adrenals) were the major toxicities, a finding which is comparable to other previously tested azole compounds. In the 4-week oral toxicity study, the lethal dose of WSA was determined to be 90 mg/kg. However, no animal mortality was observed during the 2-week intravenous continuous infusion study. The toxicokinetics (TK) profile of WSA at 10 and 30 mg/kg dosages illustrated a rapid, dose-dependent conversion of WSA to its active metabolite, and the plasma levels of Cmax and AUC were well correlated to their toxicities. However, at high dosages (60 and 90 mg/kg), WSA demonstrated high exposure beyond the dose-proportional manner. Overall, the results obtained indicate that maintaining an effective concentration and a non-toxic dosage level would be manageable by utilizing an initial intravenous continuous infusion followed by oral administration.

Administration, Oral↗

PubMed2002

Development of telemetry system in the common marmoset--cardiovascular effects of astemizole and nicardipine.

The purpose of this study was to evaluate a telemetry system for examining the cardiovascular system in the conscious common marmoset. Parameters obtained were blood pressure, heart rate, respiratory rate, ECG, body temperature and locomotor activity, and these were continuously recorded on a data recorder via the telemetry system and then processed by a computerized system. Diurnal rhythms of blood pressure, heart rate, body temperature and locomotor activity were observed in this system. We studied the effects of astemizole (antihistamine) and nicardipine (Ca2+ channel blocker) on cardiovascular parameters. Astemizole at 30 mg/kg (p.o.) and at 1 to 3 mg/kg (i.v.), prolonged QT interval and induced ventricular extrasystole. Torsades de pointes occurred in one of three cases at 3 mg/kg (i.v.) and 30 mg/kg (p.o.), while it did not affect the blood pressure, respiratory rate and body temperature. Nicardipine at 30 mg/kg (p.o.) caused sustained hypotension and tachycardia. These results demonstrate the usefulness of the telemetry system using the common marmoset for evaluating the cardiovascular effects of drugs under physiological conditions.

Animals↗

PubMedDate not supplied

Anti-beta 2-glycoprotein I autoantibodies and atherosclerosis.

beta 2-Glycoprotein I (beta 2-GPI) is a major antigen for antiphospholipid antibodies (aPL) present in patients with antiphospholipid syndrome (APS). We previously reported that beta 2-GPI specifically binds to oxidized low-density lipoprotein (oxLDL). Further, a ligand specific for beta 2-GPI, oxLig-1, purified from the extracted lipids of oxLDL was identified as 7-ketocholesterol-9-carboxynonanoate (i.e., 9-oxo-9-(7-ketocholest-5-en-3 beta-yloxy) nonanoic acid) OxLig-1 was recognized by beta 2-GPI and subsequently by anti-beta 2-GPI autoantibodies. Binding of liposomes containing oxLig-1 to macrophages were significantly enhanced in the presence of both beta 2-GPI and an anti-beta 2-GPI autoantibody derived from (NZW x BXSB) F1 mouse, an animal APS model, or from APS patients. Anti-beta 2-GPI autoantibodies derived from APS patients with episodes of arterial thrombosis were detected in ELISA, using a solid phase beta 2-GPI complex with oxLig-1. It was also reported that LDL-receptor-deficient mice that were fed a chow diet and immunized with beta 2-GPI had an accelerated atherosclerosis and that beta 2-GPI was abundantly expressed within subendothelial regions and intimal-medial borders of human atherosclerotic plaques. All of these observations strongly suggest that autoimmune atherogenesis linked to beta 2-GPI interaction with oxLDL and autoantibodies may be present in APS.

Arteriosclerosis↗

PubMedDate not supplied

IgG autoantibodies against beta2-glycoprotein I complexed with a lipid ligand derived from oxidized low-density lipoprotein are associated with arterial thrombosis in antiphospholipid syndrome.

We recently reported [J. Lipid Res. 42 (2001), 697; 43 (2002), 1486; 44 (2003), 716] that [beta2-glycoprotein I (beta2GPI) forms complexes with oxidized LDL (oxLDL) and autoantibodies against these complexes are present in patients with SLE and antiphospholipid syndrome (APS). The relationship of beta2GPI/oxLDL complexes and IgG autoantibodies against beta2GPI complexed with oxLig-1 (an oxLDL-derived ligand) with clinical manifestations of APS was studied in 150 APS and SLE patients. The beta2GPI/oxLDL levels of APS patients were similar to those of SLE patients without APS, but they were significantly higher than healthy individuals. There was no difference in the complex levels among the patients with arterial, venous thrombosis, or pregnancy morbidity. IgG anti-beta2GPI/oxLig-1 levels of APS were significantly higher than those of SLE without APS and healthy individuals. Further, antibody levels of APS patients with arterial thrombosis were significantly higher than those patients with venous thrombosis and pregnancy morbidity. Thus, oxidation of LDL leads the complex formation with beta2GPI in SLE and APS patients. In contrast, anti-beta2GPI/oxLig-1 autoantibodies were generated only in APS and were strongly associated with arterial thrombosis. These results suggest that autoantibodies against beta2GPI/oxLDL complexes are etiologically important in the development of atherosclerosis in APS.

Adolescent↗