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Articles by K Kobayashi
Total Records ( 6 ) for K Kobayashi
  K Taguchi , Y Urata , M Anraku , T Maruyama , H Watanabe , H Sakai , H Horinouchi , K Kobayashi , E Tsuchida , T Kai and M. Otagiri
 

The hemoglobin vesicle (HbV) is an artificial oxygen carrier that encapsulates a concentrated Hb solution in lipid vesicles (liposomes). The pharmacokinetic properties of HbV were investigated in mice and rats. With use of HbV in which the internal Hb was labeled with 125I (125I-HbV) and cell-free 125I-Hb, it was found that encapsulation of Hb increased the half-life by 30 times, accompanied by decreased distribution in both the liver and kidney. The half-life of HbV was increased, and the uptake clearance for the liver and spleen were decreased with increasing doses of HbV. In an in vitro study, the specific uptake and degradation of HbV in RAW 264.7 cells were found, but this was not the case for parenchymal and endothelial cells. The pharmacokinetics of HbV components (internal Hb and liposomal lipid) were also investigated using 125I-HbV and 3H-HbV (liposomal cholesterol was radiolabeled with tritium-3). The time courses for the plasma concentration curves of 125I-HbV, 3H-HbV, and iron derived from HbV suggest that HbV maintain an intact structure in the blood circulation up to 24 h after injection. 125I-HbV and 3H-HbV were distributed mainly to the liver and spleen. Internal Hb disappeared from both the liver and spleen 5 days after injection, and the liposomal cholesterol disappeared at approximately 14 days. Internal Hb was excreted into the urine and cholesterol into feces via biliary excretion. These results suggest that the HbV has a reasonable blood retention and metabolic and excretion performance and could be used as an oxygen carrier.

  K Taguchi , Y Urata , M Anraku , T Maruyama , H Watanabe , H Sakai , H Horinouchi , K Kobayashi , E Tsuchida , T Kai and M. Otagiri
 

The hemoglobin vesicle (HbV) is an artificial oxygen carrier that encapsulates a concentrated Hb solution in lipid vesicles (liposomes). The pharmacokinetic properties of HbV were investigated in mice and rats. With use of HbV in which the internal Hb was labeled with 125I (125I-HbV) and cell-free 125I-Hb, it was found that encapsulation of Hb increased the half-life by 30 times, accompanied by decreased distribution in both the liver and kidney. The half-life of HbV was increased, and the uptake clearance for the liver and spleen were decreased with increasing doses of HbV. In an in vitro study, the specific uptake and degradation of HbV in RAW 264.7 cells were found, but this was not the case for parenchymal and endothelial cells. The pharmacokinetics of HbV components (internal Hb and liposomal lipid) were also investigated using 125I-HbV and 3H-HbV (liposomal cholesterol was radiolabeled with tritium-3). The time courses for the plasma concentration curves of 125I-HbV, 3H-HbV, and iron derived from HbV suggest that HbV maintain an intact structure in the blood circulation up to 24 h after injection. 125I-HbV and 3H-HbV were distributed mainly to the liver and spleen. Internal Hb disappeared from both the liver and spleen 5 days after injection, and the liposomal cholesterol disappeared at approximately 14 days. Internal Hb was excreted into the urine and cholesterol into feces via biliary excretion. These results suggest that the HbV has a reasonable blood retention and metabolic and excretion performance and could be used as an oxygen carrier.

  Y Ozeki , I Sugawara , T Udagawa , T Aoki , M Osada Oka , Y Tateishi , H Hisaeda , Y Nishiuchi , N Harada , K Kobayashi and S. Matsumoto
 

CD4+CD25+ regulatory T (Treg) cells cause immune suppression by inhibiting T cell effector functions and play pivotal roles not only in self-tolerance but also in immune response to parasitic microbial pathogens. Mycobacteria are major parasitic bacterial pathogens, but the role of CD4+CD25+ Treg cells in mycobacterial infection is not yet defined. In this study we found that, at the early stage of infection, depletion of CD25+ cells reduced both bacterial load and granuloma formation in mice infected with Mycobacterium tuberculosis strains, such as M. tuberculosis Erdman or M. tuberculosis Kurono. However, at a later stage of infection, bacterial burden and histopathology were similar regardless of depletion of CD25+ cells. Severe combined immunodeficient (SCID) mice reconstituted with CD4+CD25 T cells alone or a combination of CD4+CD25+ and CD4+CD25 T cells showed similar bacterial loads and survival kinetics after infection with M. tuberculosis Erdman. Consistent with in vivo data, in vitro studies revealed that mycobacterial antigens, purified protein derivative of tuberculin (PPD), failed to induce the suppressive function of CD4+CD25+ Treg cells to CD4+CD25 effector T cells, as demonstrated by the lack of response of CD4+CD25+ T cells to PPD, in mice chronically infected with Mycobacterium bovis bacillus Calmette–Guérin and M. tuberculosis. Our data show that CD4+CD25+ Treg cells have a transient effect at the early stage of mycobacterial infection but, contrary to the expectation, have little impact on the overall course of infection.

  I Okamoto , T Doi , A Ohtsu , M Miyazaki , A Tsuya , K Kurei , K Kobayashi and K. Nakagawa
  Objective

To determine the pharmacokinetics and safety of RAD001 (everolimus) in Japanese patients with advanced solid tumors.

Methods

An open-label, non-randomized, dose-escalation Phase I study of RAD001 administered continuously once daily in a 28-day cycle was performed. The study had a ‘3 + 3’ design, with three patients recruited to each of three successive cohorts treated with RAD001 at 2.5, 5.0 or 10.0 mg/day.

Results

The pharmacokinetics of RAD001 in Japanese patients were similar to those previously determined in Caucasians. The drug safety profile was consistent with that of a mammalian target of rapamycin inhibitor. No dose-limiting toxicities were observed. One patient with esophageal cancer and one with gastric cancer treated with RAD001 at 10 mg/day showed marked tumor responses.

Conclusions

Treatment of Japanese cancer patients with RAD001 may be undertaken with the expectation that previously determined pharmacokinetic and safety profiles apply. The drug may hold promise for treatment of esophageal and gastric cancer.

  K Hashimoto , S. i Hisasue , N Masumori , K Kobayashi , R Kato , F Fukuta , A Takahashi , T Hasegawa and T. Tsukamoto
  Objective

We investigated the clinical safety and feasibility of an algorithm we developed for the decision-making on neurovascular bundle preservation in radical prostatectomy to decrease the incidence of positive surgical margins.

Methods

We prospectively applied our algorithm to 82 patients (164 prostate sides) with clinically localized prostate cancer who underwent radical prostatectomy at our institution between October 2004 and September 2006. The algorithm was developed using the apical core characteristics, clinical T stage, preoperative prostate-specific antigen level and Gleason sum. All prostate sides were divided into two groups by the algorithm: 115 sides (70.1%) were qualified for neurovascular bundle preservation (favorable algorithm side group) and 49 sides (29.9%) for non-neurovascular bundle preservation (unfavorable algorithm side group).

Results

Median patient age was 66 years (range: 52–77) and median prostate-specific antigen was 7.1 ng/ml (range: 1.4–29.6). Overall, a positive surgical margin was observed in 23 sides (14.0%). The incidence of positive surgical margins at the apex was significantly correlated with the maximal diameter of the tumor in the apex (P < 0.001). The incidence of positive surgical margins was 8.7% in the favorable algorithm group, whereas it was 26.5% in the unfavorable algorithm group (P = 0.003). When this algorithm was combined with surgeons' intraoperative assessments, the incidence of positive surgical margins was 2.1% in neurovascular bundle preservation sides, compared with 25.0% in non-neurovascular bundle preservation sides (P = 0.002).

Conclusions

This simple algorithm is safe and feasible for the decision-making on neurovascular bundle preservation from the aspect of cancer control in radical prostatectomy patients.

  K Kobayashi , A Tanaka , H Takahashi , J Igarashi , Y Ishitsuka , N Yokota and T. Shimizu
 

A phosphodiesterase (PDE) from Escherichia coli (Ec DOS) is a novel haem-based oxygen sensor enzyme. Binding of O2 to the reduced haem in the sensor domain enhances PDE activity exerted by the catalytic domain. Kinetic analysis of oxygen-dependent catalytic enhancement showed a sigmoidal curve with a Hill coefficient value of 2.8. To establish the molecular mechanism underlying allosteric regulation, we analysed binding of the O2 ligand following reduction of haem in the isolated dimeric sensor domain using pulse radiolysis. Spectral changes accompanying O2 binding were composed of two phases as a result of reduction of two haem complexes when high-dose electron beams were applied. In contrast, upon reduction of the dimer with a low-dose beam, the kinetics of O2 ligation displayed single-phase behaviour as a result of the reduction of one haem complex within dimer. Based on these results, we propose that the faster phase corresponds to binding of the first O2 molecule to one subunit of the dimer, followed by binding of the second O2 molecule to the other subunit. Notably, for the haem axial ligand mutant proteins, M95A and M95L, O2 binding displayed single-phase kinetics and was independent of electron beam dose.

 
 
 
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