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1.
Hiroki Koshimichi Yoshiyuki Tsuda Toru Ishibashi Toshihiro Wajima 《Journal of pharmaceutical sciences》2019,108(5):1896-1904
Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. Our aim is to characterize its pharmacokinetics and exposure-response relationships. Population pharmacokinetic analysis of the baloxavir acid was performed using 8310 plasma concentration data points from 1109 subjects. Exposure-response analyses were performed regarding the time to alleviation of symptoms and the reduction in the influenza virus titer. A 2-compartment model with first-order absorption and lag time well described the plasma concentration data for baloxavir acid, and body weight and race were found to be the most important factors influencing the clearance and distribution volume. A dose regimen based on the body weight (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg) could provide sufficient exposures for expecting efficacy irrespective of body weight or race; however, the exposures were dependent on the body weight and race. Exposure-response analyses suggested that the reduction in the influenza virus titer was greater in any exposure-based groups in baloxavir marboxil treatment than in the oseltamivir phosphate treatment and placebo groups. In conclusion, the population pharmacokinetic model and exposure-response relationships would be useful for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir acid. 相似文献
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Fumio Nakajima Tomohiko Asano Masamichi Hayakawa Hiroshi Nakamura 《International journal of urology》1996,3(1):s19-s21
We evaluated nitric oxide induction in antitumor therapy consisting of anti–CD3 monoclonal antibody (anti–CD3) and interleukin–2 (IL–2), then determined the effect of nitric oxide reduction with L–NG –monomethyl arginine (LNMA) on the therapeutic methods. Female C57BL/6 mice, MCA102 (a non immunogenic, NK–resistant murine fibrosarcoma cell line), and 145–2C11 (hamster anti–murine–CD3 mAb) were utilized in an experimental hepatic metastasis model developed by injecting a tumor cell suspension into the spleen of mice. A marked increase in serum NO2 – + NO1 was observed at 19 hours after anti–CD3 (10 μ, IV) and additional IL–2 administrations (40times101 U, twice, If) induced a further increase. The NO2 , + NO3- elevation in spot urine in the combination therapy was not suppressed with LNMA at a dose of 100 μg/h but was significantly lowered at 300 μg/h. The efficacy of the anti–CD3 + IL–2 therapy was not diminished by LNMA administration either at 100 μg/h or at 300 μg/h. 相似文献
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T. Nishikawa H. Kuwahara A. Tsuda M. Tanaka I. Koga Y. Uchida 《Human psychopharmacology》1990,5(4):363-368
Ceruletide, a potent analogue of cholecystokinin, was administered by injection to eight schizophrenics treated with neuroleptics. We examined the dose–response effect on microvibration (MV) recorded from the chin of these patients. After 15 min of bed rest, MV was recorded for 5 min as a control recording. Subsequently, saline or ceruletide, at a dose of either 0.4 m?g/kg or at 0.8 m?g/kg, was injected according to a Latin square design with an interval of 4 weeks for washing out the drug effect and MV was recorded for 30 min. MV data obtained were subjected to the fast Fourier transform and an average power spectrum was computed. A three-way analysis of variance for these data was performed upon dose-effect, time-effect after treatment, and band-effect of the average power spectrum. The present results were similar to previous findings which had revealed effects of ceruletide on tardive dyskinesia symptoms, namely, the effects of ceruletide on MV were different according to the subjects (three cases: facilitation followed by inhibition, three cases: inhibition, two cases: no effects). The dose-response curve of ceruletide appears to be linear in some cases and an inverted U-shape in other cases. Present findings showed small doses of systemically administered ceruletide would modify muscle tonus of schizophrenics under chronic treatment of neuroleptics, and provided further reason for the therapeutic drug of tardive dyskinesia. 相似文献
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Hiroyuki Yamamoto Fumio Itoh Akinori Senota Yasushi Adachi Mitsuru Yoshimoto Takao Endoh Yuji Hinoda Akira Yachi Kohzoh Imai 《Journal of clinical laboratory analysis》1995,9(5):297-301
The matrix metalloproteinase matrilysin (MMP-7) is a member of the matrix metallo-proteinase gene family, which is believed to play an important role in tumor invasion and metastasis. We have previously found that matrilysin mRNA is specifically expressed in colorectal cancers and adenomas and that its message is localized in the tumor cells themselves. We examined the effects of activated Ki-ras oncogene on the expression of matrilysin in colon cancer cells. We showed that both mRNA and the enzymatic activity of matrilysin were induced by the introduction of activated Ki-ras into SW1417 colon cancer cells. To understand the mechanisms regulating this induction, we analyzed alterations of AP-1 activity induced by activated Ki-ras, using the chloramphenicol acetyltransferase assay. AP-1 activity in SW1417 cells expressing activated Ki-ras was higher than that in control cells. The gel-shift assay also showed higher levels of AP-1 binding protein in SW1417 cells expressing activated Ki-ras than those in control cells. Our results suggest that activated Ki-ras may play a role in inducing expression of matrilysin through an AP-1-dependent pathway in colon cancer cells. 相似文献
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T Tsuda M Uchiyama T Sato H Yoshino Y Tsuchiya S Ishikawa M Ohmae S Watanabe Y Miyake 《Journal of pharmaceutical sciences》1989,78(2):91-94
The byproducts P-1 and P-2, which were produced during the synthesis of porcine secretin, were isolated in pure form from the crude secretin by HPLC. These were identified by a combination of amino acid analysis, enzymatic digestion, and isocratic or linear gradient reversed-phase (RP)-HPLC. The amino acid compositions of P1 and P2, determined by amino acid analysis after acid hydrolysis, were found to be the same as those of porcine secretin without distinction between L-and D-amino acids. But, HPLC of their digestive fragments with trypsin and alpha-chymotrypsin differed from that of secretin. The fragments, S7-12 of P-1 and S13-21 of P-2 were determined to be different from the corresponding fragments obtained from secretin by HPLC analysis of their digestive fragments. The amino acid composition of each acid hydrolysate, following digestion with D-amino acid oxidase, was found to have less leucine or alanine content than secretin. The HPLC analysis of the fragments from P-1 and P-2 by tryptic and alpha-chymotryptic digestion showed that they are the same as those from synthetic D-Leu10 secretin or D-Ala17 secretin, respectively. Consequently, P-1 and P-2 are concluded to be the secretin diastereoisomers, D-Leu10 and D-Ala17 secretin, respectively. 相似文献