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71.
72.
Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin 下载免费PDF全文
Ryoko Sawamura Hidetaka Sakurai Naoya Wada Yumi Nishiya Tomoyo Honda Miho Kazui Atsushi Kurihara Akira Shinagawa Takashi Izumi 《Biopharmaceutics & drug disposition》2015,36(6):352-363
Loxoprofen (LX) is a prodrug‐type non‐steroidal anti‐inflammatory drug which is used not only as an oral drug but also as a transdermal formulation. As a pharmacologically active metabolite, the trans‐alcohol form of LX (trans‐OH form) is generated after oral administration to humans. The objectives of this study were to evaluate the generation of the trans‐OH form in human in vitro skin and to identify the predominant enzyme for its generation. In the permeation and metabolism study using human in vitro skin, both the permeation of LX and the formation of the trans‐OH form increased in a time‐ and dose‐dependent manner after the application of LX gel to the skin. In addition, the characteristics of permeation and metabolism of both LX and the trans‐OH form were examined by a mathematical pharmacokinetic model. The Km value was calculated to be 10.3 mm in the human in vitro skin. The predominant enzyme which generates the trans‐OH form in human whole skin was identified to be carbonyl reductase 1 (CBR1) by immunodepletion using the anti‐human CBR1 antibody. The results of the enzyme kinetic study using the recombinant human CBR1 protein demonstrated that the Km and Vmax values were 7.30 mm and 402 nmol/min/mg protein, respectively. In addition, it was found that no unknown metabolites were generated in the human in vitro skin. This is the first report in which LX is bioactivated to the trans‐OH form in human skin by CBR1. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
73.
Yoshiya Adachi Yumi Yamazoe-Ishiguri Satoshi Iwata Atsushi Murase Rika Kihara Koichi Watamoto 《Internal medicine (Tokyo, Japan)》2021,60(8):1271
Though adult-onset primary autoimmune pancytopenia (AIP) rarely follows a self-limited course, a standard treatment strategy has not yet been established. We herein report two cases, each involving primary autoimmune neutropenia complicated with autoimmune thrombocytopenia or Evans syndrome. They were refractory to granulocyte-colony stimulating factor, but all lineages of cytopenia promptly recovered with prednisolone (PSL). In case 1, PSL was tapered and discontinued six months after its initiation without AIP relapse. In case 2, PSL has been tapered for five months without relapse. To establish an optimal treatment strategy for AIP, it is necessary to accumulate more cases. 相似文献
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Abstract: Although eosinophil infiltrate has been recognized in hepatic graft-versus-host disease, its significance in relation to hepatic graft-versus-host disease lesions is unknown. In the present study, we analyzed hepatic eosinophil infiltration in relation to bile duct damage in experimental mouse graft-versus-host disease across minor histocompatibility barriers up to 14 months after transplantation. Portal eosinophil infiltration was found from 1 week after transplantation throughout the entire 14-month observation period. It was most striking during the early chronic stage of hepatic graft-versus-host disease between 2 to 7 months, with a peak at 5 months after transplantation. Microscopic and electron microscopic study revealed eosinophils infiltrated around the bile duct as well as in the bile duct epithelial layer. They were commonly found together with lymphocytes but were also occasionally found singly around the bile duct and in the bile duct epithelial layer. Bile duct epithelial cells in contact with and in the vicinity of eosinophils showed a variety of degenerative changes, occasionally associated with the presence of extracellular eosinophil granules. Bile duct epithelial cells with eosinophil infiltration just beneath the basement membrane frequently showed further characteristic severe degenerative changes with shedding or dropping-off into the lumen, which features were quite similar to those seen in the bronchial epithelium in asthma patients. These results indicate that not only lymphocytes but also eosinophils may be involved in the production of the bile duct injury in hepatic graft-versus-host disease, especially in its early chronic stage. 相似文献
76.
Xiang Z Zhao Y Mitaksov V Fremont DH Kasai Y Molitoris A Ries RE Miner TL McLellan MD DiPersio JF Link DC Payton JE Graubert TA Watson M Shannon W Heath SE Nagarajan R Mardis ER Wilson RK Ley TJ Tomasson MH 《Blood》2008,111(9):4809-4812
Somatic mutations in JAK2 are frequently found in myeloproliferative diseases, and gain-of-function JAK3 alleles have been identified in M7 acute myeloid leukemia (AML), but a role for JAK1 in AML has not been described. We screened the entire coding region of JAK1 by total exonic resequencing of bone marrow DNA samples from 94 patients with de novo AML. We identified 2 novel somatic mutations in highly conserved residues of the JAK1 gene (T478S, V623A), in 2 separate patients and confirmed these by resequencing germ line DNA samples from the same patients. Overexpression of mutant JAK1 did not transform primary murine cells in standard assays, but compared with wild-type JAK1, JAK1T478S, and JAK1V623A expression was associated with increased STAT1 activation in response to type I interferon and activation of multiple downstream signaling pathways. This is the first report to demonstrate somatic JAK1 mutations in AML and suggests that JAK1 mutations may function as disease-modifying mutations in AML pathogenesis. 相似文献
77.
Tanaka T Ohtsuki Y Takechi N Suzuki K Nishibori Y Matsuo A Inoue K Fujita H Inoue N 《Journal of cardiology》2005,46(5):169-176
OBJECTIVES: This study evaluated the sensitivity and the related factors in iodine-123-beta-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) scintigraphy to detect stable angina. METHODS: The subjects were 198 patients with stable angina who underwent BMIPP before percutaneous coronary intervention or coronary bypass graft surgery. Patients with unstable angina, myocardial infarction, congestive heart failure, cardiomyopathy and vasospastic angina were excluded. After investigation of the sensitivity of BMIPP, the patients with single-vessel disease without collateral flow were classified into the normal (123)I-BMIPP uptake group (normal group)or decreased (123)I-BMIPP uptake group (decreased group), and various factors were compared between the two groups. RESULTS: Sensitivity was 61% overall, 58% in single-vessel disease, 69% in double-vessel disease, 53% in triple-vessel disease, 43% in only left main vessel disease, and 89% in left main and other vessel disease (NS). In single-vessel disease, the sensitivity was 40% in 75% coronary artery stenosis, 58% in 90% stenosis, 89% in 99% stenosis, and 69% in total occlusion (p = 0.003). Comparing the deoreased and normal groups, diabetes mellitus was more frequent in the normal group (14.6% vs 39.5%), minimal lumen diameter was smaller (0.75 +/- 0.37 vs 0.98 +/- 0.49 mm) and lesion length was longer in the decreased group (15.4 +/- 4.9 vs 11.6 +/- 5.5 mm). Logistic multivariate analysis showed that the independent factors were diabetes mellitus [odds ratio 0.20, 95% confidence interval (CI) 0.04-0.87, p = 0.03], minimal lumen diameter (odds ratio 0.10, 95% CI 0.02-0.48, p = 0.003) and lesion length (odds ratio 1.12, 95% CI 1.00-1.25, p = 0.03). CONCLUSIONS: BMIPP is useful in stable angina patients because of the acceptable sensitivity. Diabetes mellitus, minimal lumen diameter and lesion length were independent factors associated with decreased BMIPP uptake. 相似文献
78.
Hirohama D Shimizu T Hashimura K Yamaguchi M Takamori M Awatsu Y Tsujino M Mizutani T 《Internal medicine (Tokyo, Japan)》2008,47(19):1743-1746
A 58-year-old woman presented with muscle weakness, whole body myalgia, and dyspnea. On admission, neurological examination showed proximal muscle weakness in the extremities. The weakness gradually extended to the bulbar and respiratory muscles, necessitating an artificial ventilator. Serum CK level was markedly increased (33,774 IU/L; normal <150 IU/L) and myoglobinuria was noted in urinalysis. There was no sign of renal failure. Nerve conduction study was normal, but needle EMG showed myopathic changes in the weak muscles. Serological studies for virus titers showed more than a four-fold increase of cytomegalovirus (CMV) antibody titer during the disease course. The IgM anti-GM2 antibody was also elevated in the acute phase and decreased in the recovery phase. The muscle weakness and respiratory failure gradually improved after intravenous methylprednisolone administration, and the serum CK level was normalized in several days. CMV infection was thought to have played a central role in the rhabdomyolysis, leading to critical but reversible respiratory muscle paralysis. 相似文献
79.
Akatsuki Kokaze Mamoru Ishikawa Naomi Matsunaga Masao Yoshida Masao Satoh Koji Teruya Yumi Masuda Rie Honmyo Yoshiko Uchida Yutaka Takashima 《Hypertension research》2007,30(3):213-218
NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism is associated with longevity in the Japanese population, and the ND2-237Met genotype may exert antiatherogenic effects. To investigate whether ND2-237 Leu/Met polymorphism is associated with risk of hypertension, we conducted a cross-sectional study of 398 Japanese male subjects. The frequency of hypertension was significantly higher in ND2-237Leu genotypic men than in ND2-237Met genotypic men. On analysis of covariance, the interaction between ND2-237 Leu/Met polymorphism and habitual drinking was significantly associated with both systolic blood pressure and diastolic blood pressure. Multiple logistic regression analysis revealed that the ND2-237Met genotype, particularly in younger subjects (age <60 years), had a lower odds ratio for hypertension than the ND2-237Leu genotype. Moreover, the association of ND2-237 Leu/Met polymorphism with hypertension may depend on the frequency of alcohol consumption. The odds ratio for hypertension was significantly higher in daily drinkers with ND2-237Leu when compared with non- or ex-drinkers with ND2-237Leu. However, the association between the ND2-237Met genotype and hypertension may not depend on the frequency of alcohol consumption. The present results suggest that ND2-237 Leu/Met polymorphism is associated with hypertension and that modification of hypertension risk is dependent on alcohol consumption in middle-aged Japanese men. 相似文献
80.
K Kanmatsuse N Kajiwara S Onikura K Nagao Y Satoh K Yumi 《Japanese circulation journal》1988,52(7):684-694
To clarify the relationship between time interval from the onset of coronary occlusion to the reperfusion and reperfusion rates or left ventricular function, an experiment with 113 mongrel dogs was carried out. Coronary thrombi experimentally induced within 4 hours in 63 dogs were rapidly lysed by intracoronary thrombolytic agent (Experiment 1). Infarct size was investigated in 17 dogs. The infarct size (% of left ventricle) in 9 dogs with 4-hour reperfusion following 2-hour coronary occlusion was significantly smaller than that in 8 dogs with 6-hour occlusion (12.0 +/- 7.9 vs 19.1 +/- 8.7% respectively p less than 0.05) (Experiment 2). The infarct size in 8 dogs with 7-day reperfusion following 2-hour occlusion was also significantly reduced compared to that in 7 dogs with 7-day occlusion (16.3 +/- 7.4 vs 28.5 +/- 8.9%, respectively p less than 0.02) (Experiment 3). The infarct size in 11 dogs with 4-hour reperfusion with verapamil administration following 2-hour occlusion was significantly reduced compared to that in 7 dogs with 6-hour occlusion without verapamil (5.5 +/- 1.9 vs 20.3 +/- 3.3%, respectively p less than 0.01) (Experiment 4). In experiment 3, anterior wall motion also was assessed by contrast ventriculography and infarct related areas in reperfused group was found to be improved compared to non-reperfused group at 7 days after infarction. In clinical studies, 121 patients who were admitted within 12 hour of onset of symptoms, were investigated to evaluate reperfusion rates and left ventricular function. The reperfusion rate of young age thrombus within 3 hours was 89% of 18 patients with completely occluded coronary artery. It was 77% of the 52 patients with 3 to 6 hour occlusion and 72% of the 18 patients with over 6 hour occlusion. There was a tendency towards high reperfusion rates in younger thrombus. In patients who were recanalized within 3 hours from the onset of symptoms ejection fraction of left ventricle at the chronic stage had a significantly higher percentage when compared to the unsuccessful group. Wall motion of infarct-related areas in patients who were thrombolysed within 6 hours was improved compared to the unsuccessful group. Administration of verapamil during reperfusion in patients with acute myocardial infarction suppressed rapid CK release and sigma CK. Thus, young age thrombus can be lysed easily, earlier recanalization after coronary occlusion can reduce infarct size and improve left ventricular function. Reinforced administration of verapamil during reperfusion can also reduce infarct size. 相似文献