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101.
102.
Yoshihiro Mitsuhashi Yuichi Sugiyama Shogo Ozawa Takashi Nitanai Kunihiro Sasahara Kan-Ichi Nakamura Miroru Tanaka Takuzo Nishimura Makoto Inaba Tomowo Kobayashi 《Cancer chemotherapy and pharmacology》1990,27(1):20-26
Summary Plasma concentration-time profiles of nimustine hydrochloride, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), in the mouse, rat, rabbit, and dog were determined by high-performance liquid chromatographic analysis. The pharmacokinetic parameters for these four animal species and previously reported clinical data were analyzed for investigation of interspecies correlation. Loglog plots of body weight (W; kg) vs total plasma clearance (CLtot, p; ml/min) and steady-state distribution volume (Vd, ss; 1) for the four animal species were linear, with high correlation coefficients (r 0.996 for both parameters), despite the fact that the nonrenal clearance was >97% in these species. Linear regression on the plots excluding human data yielded allometric equations (CLtot,p=50.6 W0.957; Bd, ss=1.29 W1.03) that were extrapolated to predict ACNU pharmacokinetic parameters in humans. For both parameters, however, there were 3-fold differences between the predicted and observed parametric values. To investigate these discrepancies, we measured serum protein binding of ACNU in these animal species and in humans. The values of CLtot,p and Vd,ss were converted into those of CLu
tot,p and Vd,u
ss, which correspond to the parameters for unbound ACNU. In this case, correlation coefficients of the log-log plots excluding human data (CLu
tot,p=71.7 W0.891; Bd,u
ss=1.82 W0.966) were also high (r0.991). The extrapolated values vs those observed in a 70-kg human were the following: CLu
tot,p, 3,160 vs 2,290 ml/min; Vd,u
ss, 110 vs 1061. Thus, the animal data were successfully extrapolated to yield better predictions of human pharmacokinetic parameters if the analysis was based on the unbound plasma concentration of ACNU. In addition, the predicted plasma concentration-time profile for humans also showed good agreement with the observed ones. These results suggest the importance of measuring unbound fractions of drugs for more accurate prediction of human pharmacokinetic parameters by extrapolation of animal data to the human situation. 相似文献
103.
We report a case of angiosarcoma of the breast and the autopsy findings. The patient was a 35-year-old premenopausal woman
who complained of a tumor in her left breast. We found a tumor measuring 55 mm in diameter in the lower external quadrant.
The tumor was elastic and soft, smooth surfaced, well-defined and mobile. Dimpling sign or change of skin color were not observed.
Clinically it was diagnosed as phyllodes tumor, but tumorectomy revealed primary angiosarcoma of the breast. Further extended
surgery was recommended, but the patient refused additional therapy. Histological findings revealed a free surgical margin
and neither lymph node metastasis nor distant metastasis were clinically observed. Seven months later, local recurrence in
the same breast was recognized and finally radical mastectomy was carried out. Histological findings showed recurrence of
angiosarcoma in the left breast but lymph node metastasis was not detected. Two months after mastectomy, metastases to the
cervical and thoracic vertebrae were observed and radiation therapy was performed. Sixteen months from onset, she died due
to multi-organ failure as general metastases of angiosarcoma. At autopsy, metastases to many organs including the digestive
system were observed. The incidence of primary angiosarcoma of the breast is low but its prognosis is poor. This case emphasized
the difficulties in clinical diagnosis and treatment for the angiosarcoma of the breast. 相似文献
104.
Toshiro Takatori Takeshi Koizumi Taro Tokui Yoshihiro Mitsuhashi Akio Shiraishi Takashi Tsuruo 《Cancer chemotherapy and pharmacology》1995,35(4):283-290
RS-1541, an acyl-derivative of rhizoxin (Fig. 1), is a potent antitumor compound. This agent showed cytotoxicity in vitro on some cultured human tumor cells, although it was less potent than rhizoxin. Rhizoxin exhibited antitumor effects by inhibiting the polymerization of tubulin, whereas RS-1541 did not inhibit tubulin polymerization in vitro. However, cell cycle analysis in vivo showed that the two agents had the same mode of action. The cytotoxicity of RS-1541 was enhanced when the initial cell density of the cells was increased. The cytotoxicity was also enhanced when the membrane fraction of St-4 cells, which were the most sensitive to RS-1541 among the cell lines tested, was added to the target cells. When St-4 cells were incubated with [14C]-RS-1541, significant amounts of [14C]-rhizoxin were produced within the cells. Further fractionation of the crude membrane showed that the activity that enhanced the cytotoxicity of RS-1541 (RS-1541-enhancing activity) belonged to the mitochondrial-lysosomal fraction, not to the microsomal fraction. Both the enhancing activity and the activity that converting [14C]-RS-1541 to [14C]-rhizoxin (RS-1541-converting activity) were inhibited by treatment with chloroquine, an inhibitor of lysosomal function. Cholesterol esterase derived fromCandida cylindracea had RS-1541-enhancingand-converting activities. These data suggest that RS-1541 exerts its cytotoxic action after being converted to rhizoxin within the cells by a lysosomal enzyme such as cholesterol esterase.Abbreviations
DMSO
Dimethylsulfoxide
-
PBS(-) Ca2+
Mg2+-free phosphate-buffered saline
-
HCO60
hydrogenated castor oil polyethylene glycor ether
-
DMA
dimethylacetamide
-
RSB
reticulocyte standard buffer, consisting of 10mM NaCl, 1.5 mM MgCl2, and 10 mM TRIS-HCl, (pH 7.4)
-
TLC
thin-layer chromatography
-
ara-C
1--D-arabinofuranosylcytosine
-
LDL
low-density lipoprotein 相似文献
105.
Wei-dong Zhang Masataka Nagao Takehiko Takatori Kimiharu Iwadate Yoshiyuki Itakura Yoshihiro Yamada Hirotaro Iwase Tsuneaki Oono 《International journal of legal medicine》1995,107(4):174-178
This paper investigates the immunohistochemical dynamics of leukotoxin (9,10-epoxy-12-octadecenoic acid, LTx) in the lungs of rats exposed to hyperoxia with or without paraquat. The rats were treated with 100% oxygen or ambient air for 24. 48, 72 and 96 h in the presence or absence of a low or high dose paraquat (1,1-di-methyl-4,4-bipyridinium, PQ) injection. Immunostaining for LTx demonstrated positive reactions in the neutrophils that showed a progressive increase in intensity of staining with time in all groups exposed to 100% oxygen and in the group with high dose PQ, but the positive findings were weak in the group injected with low dose PQ only. We found the positive immunostaining reaction not only in neutrophils but also in alveolar macrophages. This indicates that LTx is produced by alveolar macrophages as well as by neutrophils depending on the treatment period under hyperoxic conditions, suggesting that LTx is an important chemical mediator in pulmonary diseases. 相似文献
106.
为了解GB病毒C(GBV-C)感染与肝细胞癌(下称肝癌)之间可能的相关性,采用一步法逆转录聚合酶链反应(RT-PCR)对124 例肝癌患者进行了GBV-CRNA 检测。结果:GBV-CRNA 总检出率高达26.6% (33/124),33 例GBV-CRNA 检出阳性者中,90.9% 合并有HBV、HCV感染;33 例非B非C型肝癌中,GBV-CRNA检出率为9.1% (3/33)。33 例GBV-C感染阳性肝癌患者中,90.0% (30/33)有既往输血史,高于GBV-C感染阴性组(48/91)。上述结果提示,我国肝癌患者中GBV-C感染的检出率高于美、欧、日等地同类患者的检出率,其在肝细胞癌及输血后肝炎发生中的病因学意义值得注意。 相似文献
107.
108.
Liver Targeting of Interferon Through Pullulan Conjugation 总被引:1,自引:0,他引:1
Xi Keli Tabata Yasuhiko Uno Kazuko Yoshimoto Miwa Kishida Tsunataro Sokawa Yoshihiro Ikada Yoshito 《Pharmaceutical research》1996,13(12):1846-1850
Purpose. The purpose of this study was to actively target interferon (IFN) to the liver through its chemical conjugation with pullulan, a water-soluble polysaccharide with a high affinity for the liver.
Methods. Chemical conjugation of IFN with pullulan was achieved by a cyanuric chloride method. Following intravenous injection of the conjugates to mice, their body distribution and the activity of an IFN-induced enzyme, 2,5-oligoadenylate (2-5A) synthetase in the liver and other organs, were evaluated.
Results. The cyanuric chloride method enabled us to prepare an IFN-pullulan conjugate that retained approximately 7–9 % of the biological activity of IFN. Pullulan conjugation enhanced the liver accumulation of IFN and the retention period with the results being reproducible. When injected intravenously to mice, the IFN-pullulan conjugate enhanced the activity of 2-5A synthetase in the liver. The activity could be induced at IFN doses much lower than those of free IFN injection. In addition, the liver 2-5A synthetase induced by conjugate injection was retained for 3 days, whereas it was lost within the first day for the free IFN-injected mice.
Conclusions. IFN-pullulan conjugation was promising for IFN targeting to the liver with efficient exertion of its antiviral activity therein. 相似文献
109.
Terashima Keisuke Takai Satomi Usami Yoshiko Adachi Tetsuo Sugiyama Tadashi Katagiri Yoshihiro Hirano Kazuyuki 《Pharmaceutical research》1996,13(9):1327-1330
Purpose. Indomethacin is well known to be metabolized via O-demethylation and N-deacylation. In this paper we found an enzyme involved in the hydrolysis of amide-linkage of indomethacin and partially characterized it as well as its substrate specificity.
Methods. An indomethacin hydrolyzing enzyme was purified to homogeneity from pig liver microsomes using columns of Q-Sepharose, Red-Sepharose and Blue-Sepharose. The enzyme activity was assayed by measuring of -chlorobenzoic acid liberated from indomethacin by HPLC.
Results. The purified enzyme effectively hydrolyzed the amide linkage in indomethacin but not those in -naphthylacetate and -nitrophenylacetate, which are typical substrates for carboxylesterase. The subunit molecular mass of the enzyme was 65 kDa according SDS-polyacrylamide gel electrophoresis. The Michaelis constant (Km) and maximum velocity (Vmax) values for indomethacin were 67.8 µM and 9.02 nmol/min/mg protein, respectively. The amino acid sequence analysis of the enzyme after cyanogen bromide cleavage showed high homology with a mouse carboxylesterase isozyme designated as ES-male. The activity of indomethacin hydrolysis was relatively high in the pig, rabbit and human liver homogenate, but not in those from rat and mouse. On the other hand, purified human liver carboxylesterases pl 5.3 and 4.5, and pig liver carboxylesterases have no catalytic activity for indomethacin.
Conclusions. These results indicate that the hydrolysis of amide-linkage of indomethacin in humans would be associated with an enzyme similar to the indomethacin hydrolyzing enzyme from pig liver microsomes described here. 相似文献
110.
Delayed image of iodine-123 iomazenil as a relative map of benzodiazepine receptor binding: The optimal scan time 总被引:2,自引:0,他引:2
Yoshihiro Onishi Yoshiharu Yonekura Fumiko Tanaka Sadahiko Nishizawa Hidehiko Okazawa Koichi Ishizu Toru Fujita Junji Konishi Takao Mukai 《European journal of nuclear medicine and molecular imaging》1996,23(11):1491-1497
Delayed single-photon emission tomograpic (SPET) images after an intravenous bolus injection of iodine-123 iomazenil have been used as a relative map of benzodiazepine receptor binding. We determined the optimal scan time for obtaining such a map and assessed the errors of the map. SPET and blood data from six healthy volunteers and five patients were used. A three-compartment kinetic model was employed in simulation studies and analyses of actual data. The simulation studies suggested that, in the normal brain, the scan time at which a single SPET image best represented the relative receptor binding was 3.0–3.5 h post-injection. This finding was supported by actual data from the volunteers. The simulation studies also suggested that the optimal scan time was not greatly changed by the variability of the input functions, and that the error in the SPET image contrast in the vicinity of the optimal scan time was not increased by changes in the tracer kinetics in the entire brain. The SPET image contrast in the patients at 3.0 h post-injection agreed well with the reference receptor binding estimated by kinetic analysis, with a mean error of 3.6%. These findings support the use of a single SPET image after bolus injection of [123I]iomazenil as a relative map of benzodiazepine receptor binding. For this purpose, a SPET scan time of 3.0-3.5 h post-injection is recommended. 相似文献