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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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Kei Kamide Yoshihiro Kokubo Hironori Hanada Junko Nagura Jin Yang Shin Takiuchi Chihiro Tanaka Mariko Banno Yoshikazu Miwa Masayoshi Yoshii Tetsutaro Matayoshi Hisayo Yasuda Takeshi Horio Akira Okayama Hitonobu Tomoike Yuhei Kawano Toshiyuki Miyata 《Hypertension research》2006,29(4):243-252
Mutations in the gene encoding 11beta-hydroxysteroid dehydrogenase type 2, HSD11B2, cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, defective HSD11B2 enzyme activity results in overstimulation of the mineralocorticoid receptor (MR) by cortisol, causing sodium retention, hypokalemia, and salt-dependent hypertension. Here, we have studied whether genetic variations in HDS11B2 are implicated in essential hypertension in Japanese hypertensives and the general population. By sequencing the entire coding region and the promoter region of HDS11B2 in 953 Japanese hypertensives, we identified five missense mutations in 11 patients (L14F, n = 5; R74H, n = 1; R147H, n = 3; T156I, n = 1; R335H, n = 1) and one novel frameshift mutation (4884Gdel, n = 1) in a heterozygous state, in addition to 19 genetic variations. All genetic variations identified were rare, with minor allele frequencies less than 0.005. Four of 12 patients with the missense/frameshift mutations showed renal failure. Four missense mutations, L14F, R74H, R147H, and R335H, were successfully genotyped in the general population, with a sample size of 3,655 individuals (2,175 normotensives and 1,480 hypertensives). Mutations L14F, R74H, R147H, and R335H were identified in hypertensives (n = 6, 8, 3, and 0, respectively) and normotensives (n = 8, 12, 5, and 0, respectively) with a similar frequency, suggesting that these missense mutations may not strongly affect the etiology of essential hypertension. Since the allele frequency of all of the genetic variations identified in this study was rare, an association study was not conducted. Taken together, our results indicate that missense mutations in HSD11B2 do not substantially contribute to essential hypertension in Japanese. 相似文献
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Toshio Imaizumi MD PhD Toshimi Honma MD PhD Yoshifumi Horita MD Ikuhide Kohama MD PhD Kei Miyata MD Maiko Kawamura MD Jun Niwa MD PhD 《Journal of neuroimaging》2006,16(3):236-242
BACKGROUND AND PURPOSE: Dot-like low intensity spots (dot-like hemosiderin spots: dotHSs) on gradient echo T2*-weighted MRI have been histologically diagnosed to represent old cerebral microbleeds associated with microangiopathies. They have also been correlated to the fragility of small vessels and the tendency to bleed. Therefore, a substantial number of dotHSs might be associated with a large-sized, deep intracerebral hematoma (ICH). On the other hand, dotHSs may reflect old microbleeds that did not enlarge to symptomatic size. METHODS: To investigate how dotHSs are related to the size (maximal diameter) of primary deep ICH, we analyzed the diameter and the number of dotHSs in 151 patients with deep ICH not associated with subarachnoid hemorrhage or intraventricular hemorrhage (75 males and 76 females, age ranged from 37 to 90 [65.7 +/- 11.3 years old] who were consecutively admitted to Hakodate Municipal Hospital. The hazard ratio (HR) for a maximal diameter of deep ICH < or =2 cm was estimated, using the number of dotHSs and risk factors for stroke. RESULTS: The number of dotHSs associated with the diameter < or =2 cm was 9.2 +/- 11.5, significantly larger than that with the diameter > or =2 cm (4.7 +/- 7.0, P= .012). Multivariate analysis revealed that a maximal diameter of deep ICH of < or =2 cm was found in patients with dotHS (HR, 3.7; 95% confidence interval [CI], 1.4-10.1; P= .009). CONCLUSION: Though small sample size limited the power of our analyses, these findings suggest that the number of dotHSs may be associated with a small diameter of deep ICH. 相似文献
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Twenty-one mature New Zealand white female rabbits were allocated into three groups of seven rabbits. Group I received a bolus of doughy Simplex polymethylmethacrylate (PMMA) cement injected into the proximal tibia through a drill hole. Group II received a preformed, cooled, bulk PMMA pellet. Group III had particulate PMMA powder implanted. The operated, but nonimplanted, left tibiae served as controls. Animals were killed after four months. Histologically, both Group I and Group II demonstrated a thin, fibrous tissue membrane at the implant interface. Particulate PMMA (Group III) stimulated a much thicker, florid, foreign body reaction composed of histiocytes and giant cells. The foreign body response to particulate acrylic cement was similar to that seen in failed cemented joint replacement arthroplasty in humans. 相似文献
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Y Abiko K Ichihara K Sakai H Sashida T Ishibashi 《Methods and findings in experimental and clinical pharmacology》1986,8(5):271-278
This paper describes a method by which antianginal drugs can be evaluated in the dog heart in situ. Myocardial pH was measured continuously by a micro glass pH electrode inserted in the left ventricular endocardial layers of the dog anesthetized with pentobarbital. Occlusion of the left anterior descending coronary artery (LAD) decreased myocardial pH, and release of the LAD restored the pH. The myocardial acidosis induced by ischemia was metabolic in nature and accompanied by a decrease in the levels of adenosine triphosphate and creatine phosphate and an increase in the levels of lactate in the myocardium. Drugs were injected intravenously 30 min after incomplete (partial) occlusion ot the LAD, lasting until 60 min after drug injection. Propranolol, atenolol, and sotalol markedly attenuated the myocardial pH that had been decreased by LAD occlusion. Nitroglycerin, diltiazem, and nicorandil also attenuated the pH, but these drugs were less active in attenuating myocardial acidosis. Dipyridamole, nifedipine, and beta-2 adrenoceptor antagonists were least active in this regard. It is concluded that myocardial pH can be used as an indicator of myocardial regional ischemia and utilized for evaluation of antianginal drugs. 相似文献