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81.
Morita Y Sakaeda T Horinouchi M Nakamura T Kuroda K Miki I Yoshimura K Sakai T Shirasaka D Tamura T Aoyama N Kasuga M Okumura K 《Pharmaceutical research》2003,20(4):552-556
Purpose. Recent clinical studies suggest the importance of the MDR1 genotype at position 3435 (C3435T) in terms of pharmacokinetics, but there is still no consensus in reports on the relationship between the genotype and plasma/serum concentration-time profiles of drugs after conventional oral administration. This study was performed to elucidate the effects of C3435T on the rate of duodenal absorption of digoxin in healthy Japanese subjects.
Methods. Digoxin solution was sprinkled directly over the surface of the duodenum using an endoscope, and its absorption rate was evaluated by serial monitoring of the serum concentration and by analysis of its initial 15-min increasing phase.
Results. The duodenal absorption rates of digoxin were 911 ± 91 ng/min and 506 ± 76 ng/min for C/C and T/T, respectively (±SE, p = 0.007).
Conclusions. The C3435T mutation of the MDR1 gene is associated with suppression of duodenal absorption of digoxin. 相似文献
82.
Effects of reactive oxygen species on cell proliferation and death in HeLa cells and its MDR1-overexpressing derivative cell line 总被引:1,自引:0,他引:1
Liu YW Sakaeda T Takara K Nakamura T Ohmoto N Komoto C Kobayashi H Yagami T Okamura N Okumura K 《Biological & pharmaceutical bulletin》2003,26(2):278-281
In this paper, the effects of H2O2, a typical reactive oxygen species (ROS), on cell proliferation or death were examined using the human cervical carcinoma cell line HeLa and its MDR1-overexpressing subline, Hvr100-6, which was established by stepwise exposure to vinblastine. It was confirmed that the growth of HeLa cells was enhanced by H2O2 at relatively low concentrations in a concentration-dependent manner, and the growth enhancement was suppressed by antioxidants. Doxorubicin and daunorubicin also enhanced the growth of HeLa cells at concentrations lower than IC50 values, and the antioxidants suppressed this effect, being consistent with the fact that both anticancer drugs generate ROS. The growth enhancement by H2O2 or doxorubicin and daunorubicin was not observed in Hvr100-6 cells. In addition, it was suggested that antioxidants had no effect on MDR1 mRNA expression in HeLa and Hvr100-6 cells, and thereby hardly reverse multidrug resistance in tumor cells. 相似文献
83.
Ueda K Yamazaki Y Teshima Y Yamashita C Sakaeda T Iwakawa S 《Journal of drug targeting》2003,11(4):241-246
Previously, we prepared lipid emulsions with soybean oil (SO; 20%) as oil phase and hydrogenated castor oils (HCOs; 2.4%) as emulsifiers (SO(20)/HCOs(2.4)), and found that the lipid emulsions prepared with HCO of 10 oxyethylene units (SO(20)/HCO10(2.4)) were quickly cleared from the plasma, while those prepared with HCO of 20 oxyethylene units (SO(20)/HCO20(2.4)) showed prolonged plasma circulation of the incorporated drug (Ueda et al., 2003). In the present study, the pharmacokinetics of menatetrenone incorporated into SO/HCO10s and SO/HCO20s of different particle sizes (100-280 nm), obtained by altering the SO contents, were examined in rats. The plasma half-lives of menatetrenone as SO/HCO10s were similar to each other, irrespective of particle size, even though the liver uptake of menatetrenone as SO(2.5)/HCO10(2.4) was larger than that as SO(20)/HCO10(2.4). The menatetrenone half-lives were also similar to each other for SO/HCO20s. The pretreatment with dextran sulfate 500,000 (DS500), a suppressor of the reticuloendothelial system (RES), increased the plasma concentration and inhibited the liver uptake of menatetrenone as SO/HCO10s, but not for those as SO/HCO20s. These findings indicated that the particle sizes did not affect the minimum oxyethylene units within HCOs for the prolonged plasma circulation of menatetrenone as SO/HCOs, which was 20. 相似文献
84.
Yagami T Ueda K Asakura K Sakaeda T Hata S Kuroda T Sakaguchi G Itoh N Hashimoto Y Hori Y 《Brain research》2003,960(1-2):71-80
Secretory phospholipase A2 (sPLA2) exhibits neurotoxicity in the central nervous system. There are high-affinity binding sites of the porcine pancreatic group IB sPLA2 (sPLA2-IB) in the brain. sPLA2-IB causes neuronal cell death via apoptosis in the rat cerebral cortex. Although apoptosis is triggered by an influx of Ca2+ into neurons, it has not yet been ascertained whether the Ca2+ influx is associated with the neurotoxicity of sPLA2-IB. We thus examined the possible involvement of Ca2+ in the neurotoxicity of sPLA2-IB in the primary culture of rat cortical neurons. sPLA2-IB induced neuronal cell death in a concentration- and time-dependent manner. This death was accompanied by condensed chromatin and fragmented DNA, exhibiting apoptotic features. Before apoptosis, sPLA2-IB markedly enhanced the influx of Ca2+ into neurons. A calcium chelator suppressed neurons from sPLA2-IB-induced neuronal cell death in a concentration-dependent manner. An L-type voltage-sensitive Ca2+ channel (L-VSCC) blocker significantly protected the sPLA2-IB-potentiated influx of Ca2+. On the other hand, blockers of N-VSCC and P/Q-VSCC did not. An L-VSCC blocker protected neurons from sPLA2-IB-induced neuronal cell death. In addition, the L-VSCC blocker ameliorated the apoptotic features of sPLA2-IB-treated neurons. Neither an N-VSCC blocker nor P/Q-VSCC blockers affected the neurotoxicity of the enzyme. In conclusion, these findings demonstrate that the influx of Ca2+ into neurons play an important role in the neurotoxicity of sPLA2-IB. Furthermore, the present study suggests that L-VSCC contribute to the sPLA2-IB-potentiated influx of Ca2+ into neurons. 相似文献
85.
Effects of carvedilol on MDR1-mediated multidrug resistance: comparison with verapamil 总被引:2,自引:0,他引:2
Kakumoto M Sakaeda T Takara K Nakamura T Kita T Yagami T Kobayashi H Okamura N Okumura K 《Cancer science》2003,94(1):81-86
The reversing effects of carvedilol and other β-adrenoceptor antagonists on multidrug resistance (MDR) were assessed in HeLa cells and the MDR1-overexpressing derivative Hvr100–6 cells, established by stepwise increases of vinblastine concentration in the culture medium. The inhibitory effects on the transcellular transport and intracellular accumulation of [3 H]vinblastine and [3 H]daunorubicin were also assessed using LLC-GA5-COL150 cell monolayers, established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC-PK, cells. The cytotoxic effects of vinblastine, paclitaxel, doxorubicin and daunorubicin in Hvr100–6 were reversed 1.4- to 7.1-fold by carvedilol at the realistic clinical concentration of 1 μM , whereas other β-adrenoceptor antagonists had weaker or no such effects. Transport experiments using LLC-GA5-COL150 cell monolayers demonstrated that this effect of carvedilol was due to the inhibition of MDR1-mediated transport of vinblastine, paclitaxel, doxorubicin and daunorubicin. These MDR1-mediated reversing effects of carvedilol were similar to those of 1 μM verapamil, suggesting that carvedilol could be a candidate modulator of MDR in clinical use. Since other β-adrenoceptor antagonists had no inhibitory effect on transport, the effects of carvedilol were not related to β-adrenoceptors and might have been due to antioxidant activity. (Cancer Sci 2003; 94: 81–86) 相似文献
86.
Sakaeda T Yamamori M Kuwahara A Hiroe S Nakamura T Okumura K Okuno T Miki I Chayahara N Okamura N Tamura T 《Therapeutic drug monitoring》2008,30(4):497-503
This study was conducted to evaluate the association between systemic exposure to 5-fluorouracil (5-FU) and genetic polymorphisms of vascular endothelial growth factor (VEGF) with clinical outcomes to a 5-FU/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma (ESCC). Forty-nine patients with ESCC (I/II/III/IVa = 11/9/17/7, with 5 postoperative recurrences) were enrolled into this study. One course of treatment consisted of protracted venous infusions of 5-FU (400 mg/m2/24 hr for day 1-5 and 8-12) and cisplatin (40 mg/m2/3 hr on day 1 and 8), and radiation (2 Gy/day on day 1-5, 8-12, and 15-19); a second course was repeated after a 2 week interval. A total of eight measurements of the plasma concentration of 5-FU were made per patient to evaluate its systemic exposure as area under the concentration time curve for 480 hours (AUC480h), and VEGF genotypes of T-1498C, G-1154A, C-634G, C-7T, C936T, and G1612A were evaluated. The mean value of AUC480h in the patients with a complete response was 58.7 +/- 16.8 mg*h/L, which was higher than that in the others, 49.0 +/- 10.9 mg*h/L (P = 0.029), whereas no such association was found for severe acute toxicities. VEGF genotype was not associated with the clinical response, whereas VEGF G-1154A resulted in severe acute leukopenia (P = 0.042) and severe acute cheilitis (P = 0.025). In conclusion, VEGF G-1154A was a predictor of severe acute toxicities during 5-FU/cisplatin-based chemoradiotherapy in Japanese ESCC patients, whereas the AUC480h value of 5-FU was predictive of the clinical response. 相似文献
87.
Kyoko Seki Yasuo Tsuduki Takeshi Ioroi Michiko Yamane Hiroko Yamauchi Yukinari Shiraishi Tadaaki Ogawa Izumi Nakata Kohshi Nishiguchi Teruhisa Matsubayashi Yoshihide Takakubo Motohiro Yamamori Akiko Kuwahara Noboru Okamura Toshiyuki Sakaeda 《International journal of medical sciences》2014,11(6):641-645
Objective: Clinical laboratory test data obtained prior to treatments were previously analyzed from the standpoint of susceptibility to hypersensitivity reactions in patients treated with the platimun anticancer agent, oxaliplatin (L-OHP). In the present study, the time course from the first to last cycle of the treatment was additionally analyzed to determine a better predictor of these reactions.Methods: A total of 20 laboratory test data were obtained from 108 Japanese patients with advanced colorectal cancer who were treated with the L-OHP-containing regimens, FOLFOX4 and/or mFOLFOX6. The averages and variation coefficients (CV%) of the data until the last cycle of the treatment were compared between patients with hypersensitivity reactions and those without.Results: The average serum lactate dehydrogenase (LDH) level was lower in patients with grade 1/2 reactions (P=0.016), whereas its CV% value was higher in patients with grade 3/4 reactions (P=0.005) than in those without reactions. An increase in serum LDH levels was observed in some patients with grade 3/4 reactions as the cycle number increased, and thereafter hypersensitivity reactions occurred. This phenomenon was not always observed, but was never detected in patients with grade 1/2 reactions.Conclusions: Serum LDH levels may be a predictive marker of hypersensitivity reactions in patients treated with L-OHP. Further extensive examinations with a larger number of patients are needed to establish a patient management strategy. 相似文献
88.
Tamura T Kuwahara A Kadoyama K Yamamori M Nishiguchi K Inokuma T Takemoto Y Chayahara N Okuno T Miki I Fujishima Y Sakaeda T 《International journal of medical sciences》2011,8(5):406-412
Objectives: The irinotecan (CPT-11) + 5-fluorouracil (5-FU)/leucovorin (LV) + UFT/LV chemotherapy, in which repetitive oral administration of UFT/LV replaces the infusion of 5-FU/LV in the FOLFIRI regimen, has been proposed previously. In this study, five of 10 patients were injected with a bolus of 5-FU and the other were not injected with it in order to examine the effect of omitting it in terms of pharmacokinetics of 5-FU.Methods: The treatment consisted of the intravenous infusions of CPT-11 at 100 mg/m2 and l-LV at 15 mg/m2, and the injection of a bolus of 5-FU at 500 mg/m2 on day 1, and the repetitive oral administration of UFT/LV (300 mg/m2/day as tegafur + 75 mg/day of LV) on days 1-5. A total of 13 measurements of the plasma concentrations of uracil, 5-FU and tegafur were made per patient within 48 hr after the start of chemotherapy and the value of area under the concentration-time curve (AUC0-48) was evaluated. The plasma concentration was also determined at 2 weeks to assess long-term exposure to 5-FU.Results: The plasma concentrations of 5-FU at 24 hr after the start of treatment were 27.4 ng/mL and 9.4 ng/mL in the patients with and without the bolus injection, respectively. At 48 hr, they were 31.3 ng/mL and 10.4 ng/mL with the AUC0-48 values of 22.16 mg*h/L and 0.65 mg*h/L, respectively. The 5-FU was detected in the plasma at 226 hr after the last administration of UFT/LV for the patients with the bolus injection, but not for those without.Conclusion: A bolus of 5-FU on day 1 provided long-term exposure to 5-FU. 相似文献
89.
Ikuya Miki Tsutomu Nakamura Akiko Kuwahara Motohiro Yamamori Kohshi Nishiguchi Takao Tamura Tatsuya Okuno Hideaki Omatsu Shigeto Mizuno Midori Hirai Takeshi Azuma Toshiyuki Sakaeda 《International journal of medical sciences》2012,9(9):748-756
Objective: Chemotherapy-related toxicities are difficult to predict before treatment. In this study, we investigated whether thyroid hormone receptor beta (THRB) genetic polymorphisms can serve as a potential biomarker in patients with esophageal squamous cell carcinoma (ESCC).Methods: Forty-nine Japanese patients with ESCC who received a definitive chemoradiotherapy (CRT) with 5-fluorouracil and cisplatin in conjunction with concurrent irradiation were retrospectively analyzed. Severe acute toxicities, including leukopenia, stomatitis, and cheilitis, were evaluated according to 6 single nucleotide polymorphisms (SNPs) in the gene; the intronic SNPs of rs7635707 G/T, rs6787255 A/C, rs9812034 G/T, and rs9310738 C/T and the SNPs in the 3′-untranslated region (3′-UTR) of rs844107 C/T and rs1349265 G/A.Results: Distribution of the 4 intronic SNPs, but not the 2 SNPs in the 3′-UTR, showed a significant difference between patients with and without severe acute leukopenia. Stomatitis and cheilitis were not associated with any of the 6 analyzed SNPs. Frequency of haplotype of the 4 intronic SNPs reached approximately 97% with the 2 major haplotypes G-A-G-C (73.4%) and T-C-T-T (23.5%).Conclusions: THRB intronic SNPs can provide useful information on CRT-related severe myelotoxicity in patients with ESCC. Future studies will be needed to confirm these findings. 相似文献
90.
Objective: Adverse event reports (AERs) submitted to the US Food and Drug Administration (FDA) were reviewed to assess the bleeding complications induced by the administration of antiplatelets and to attempt to determine the rank-order of the association.Methods: After a deletion of duplicated submissions and the revision of arbitrary drug names, AERs involving warfarin, aspirin, cilostazol, clopidogrel, ethyl icosapentate, limaprost alfadex, sarpogrelate, and ticlopidine were analyzed. Authorized pharmacovigilance tools were used for the quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean.Results: Based on 22,017,956 co-occurrences, i.e., drug-adverse event pairs, found in 1,644,220 AERs from 2004 to 2009, 736 adverse events were listed as warfarin-associated adverse events, and 147 of the 736 were bleeding complications, including haemorrhage and haematoma. Both aspirin and clopidogrel were associated with haemorrhage, but the association was more noteworthy for clopidogrel. As for bleeding complications related to the gastrointestinal system, e.g., melaena and haematochezia, the statistical metrics suggested a stronger association for aspirin than clopidogrel. The total number of co-occurrences was not large enough to compare the association with bleeding complications for the other 5 antiplatelets.Conclusions: The data strongly suggest the necessity of well-organized clinical studies with respect to antiplatelet-associated bleeding complications. 相似文献