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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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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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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
7.
Yukihisa Fukuda Savio L-Y Woo John C Loh Eiichi Tsuda Peter Tang Patrick J McMahon Richard E Debski 《Journal of orthopaedic research》2003,21(6):1107-1112
The loads needed to elicit a positive pivot shift test in a knee with an anterior cruciate ligament (ACL) rupture have not been quantified. The coupled anterior tibial translation (ATT), coupled internal tibial rotation (ITR), and the in situ force in the ACL in response to a valgus torque, an inherent component of the pivot shift test, were measured in 10 human cadaveric knee specimens. Using a robotic/universal force-moment sensor testing system, valgus torques ranging from 0.0 to 10.0 Nm were applied in nine increments on the intact and ACL-deficient knee in flexion ranging from 0 degrees to 90 degrees. At 15 degrees of knee flexion, the coupled ATT and ITR were significantly increased in the ACL-deficient knee when compared to the intact knee. Coupled ATT increased a maximum of 291% (6.7 mm, p<0.05), while coupled ITR increased a maximum of 85% (5.1 degrees, p<0.05). At 30 degrees, the increases in coupled ATT and ITR were significant at valgus loads of 3.3 Nm and greater with a maximum increase in coupled ATT of 137% (6.3 mm, p<0.05) and a maximum increase in coupled ITR of 38% (3.6 degrees, p<0.05). At 45 degrees, coupled ATT increased significantly (maximum of 69%, 4.4 mm, p<0.05), but only at torques > or =6.7 Nm. The in situ force in the ACL was less than 20 N for all flexion angles when a torque between 3.3 and 5.0 Nm was applied. Low valgus torque elicited tibial subluxation in the ACL-deficient knee with low in situ ACL forces, similar to a positive pivot shift test. Thus, application of a valgus torque may be suitable to evaluate ACL-deficient and ACL-reconstructed knees, since subluxation can be achieved with minimal harm to the ACL graft. This work is important in understanding one load component needed for the pivot shift examination; further studies quantifying other load components are essential for better comprehension of the in vivo pivot shift examination. 相似文献
8.
Kazushi Tsuda Keizo Kimura Hiroki Shima Ichiro Nishio Yoshiaki Masuyama 《Clinical and experimental pharmacology & physiology》1992,19(7):531-535
The present study was designed to investigate the presynaptic alpha 2-adrenoceptor function to inhibit norepinephrine (NE) release in blood vessels of reduced renal mass salt hypertensive rats (Na-loaded HT). Isolated perfused mesenteric vasculatures were prepared from Na-loaded HT and normotensive control rats (NT-control), and the NE release and vascular responsiveness were examined. Periarterial nerve stimulation caused a significantly greater release of NE and pressor responses in Na-loaded HT than in NT-control. Yohimbine, a potent alpha 2-adrenoceptor antagonist, demonstrated the facilitatory effects on NE release during nerve stimulation. The effects were significantly attenuated in Na-loaded HT compared with NT-control. These results demonstrate that vascular sympathetic nervous activity might be enhanced in Na-loaded HT. Furthermore, the increased NE release from vascular adrenergic neurons in Na-loaded HT could partially depend on impaired presynaptic alpha 2-adrenoceptor-mediated modulation, which might contribute to the pathogenesis and maintenance of this form of salt-dependent hypertension. 相似文献
9.
One of the most problematic aspects of surgery for hepatocellular carcinoma (HCC) is the frequent development of multiple tumors. Determination of the origin of multiple tumors, i.e., multifocal or metastatic, is important for predicting the clinical course of the disease after surgery. In order to clarify the origin of multiple tumors of HCC genetically, we examined patterns of loss of heterozygosity (LOH) on chromosome 16 for DNA isolated from 43 HCCs resected from 19 patients by analysis of restriction fragment length polymorphism. The cases were classified macro- and microscopically into 3 groups: multifocal origin; metastatic origin; and undetermined. Classification based on morphological features was shown to be well correlated with patterns of LOH in multiple tumors of HCC. Different patterns of LOH on chromosome 16 were detected in 8 of 11 patients with tumors of morphologically multifocal origin, whereas they were detected in none of 5 patients with tumors of morphologically metastatic origin. Among five patients with tumors of morphologically undetermined origin, a difference of LOH pattern among the tumors was detected in two, whereas in the other three, the pattern was identical between the tumors. A different pattern of LOH among HCCs arising in situ showed that they were composed of different clones, strongly suggesting their independent clonal origin and multifocal development. These results show that not only appropriate morphological observation but also examination of the LOH pattern on a particular chromosome is useful in diagnosis of multifocal HCC. 相似文献
10.
Effects of herbal medicine Dai-Kenchu-to on anorectal function in children with severe constipation.
AIM: We administered the herbal medicine Dai-Kenchu-To (DKT) to children with severe chronic constipation or with severe constipation after surgery for anorectal malformations. We then objectively assessed the effect of DKT on anorectal function by manometric study in addition to using a clinical scoring system. PATIENTS AND METHODS: Ten children with severe chronic constipation and 5 children with severe constipation after surgery for anorectal malformations were assessed. These 15 children received 0.3 g/kg/day of DKT for periods ranging from 3 months to 1 year. We objectively assessed their bowel function, sphincter function and rectal reservoir function by anorectal manometry and clinical scoring. RESULTS: In 10 children with severe chronic constipation, the clinical score after administration of DKT (7.2 +/- 0.8) improved significantly compared with that before administration of DKT (4.6 +/- 2.9) (p < 0.02). The threshold sensation volume and the maximum tolerable volume after administration of DKT significantly (p < 0.05; p < 0.01) decreased (128 +/- 63 ml vs. 69 +/- 18 ml; 229 +/- 99 ml vs. 144 +/- 47 ml), and rectal compliance after administration of DKT also significantly (p < 0.05) decreased (12.4 +/- 10.9 ml/cmH(2)O vs. 4.7 +/- 3.9 ml/cmH(2)O). CONCLUSION: The present study demonstrated that DKT had a favorable clinical effect on severe constipation in children, and anorectal manometry showed an improvement in their rectal reservoir functions. It appears that the results were secondary to DKT-stimulated peristalsis of the intestine, which promoted regular bowel habits. 相似文献