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Articles by H Nakayama
Total Records ( 8 ) for H Nakayama
  K Fujita , H Nakayama , W Ichikawa , W Yamamoto , H Endo , F Nagashima , R Tanaka , T Miya , Y Sunakawa , K Yamashita , K Mizuno , H Ishida , K Araki , M Narabayashi , K Miwa , Y Ando , Y Akiyama , K Kawara , T Hirose and Y. Sasaki
 

S-1 is an oral anticancer agent that combines tegafur, a prodrug of 5-fluorouracil (5-FU), and 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase. We examined the effects of aging on the pharmacokinetics of the components of S-1. The median area under the concentration-time curve (AUC) of active 5-FU did not significantly differ between 10 patients 75 years or older and 53 patients younger than 75 years (P = 0.598, Mann-Whitney U test). It is interesting to note that the median oral clearance of tegafur in patients 75 years or older was significantly lower than that in patients younger than 75 years (P = 0.011). Furthermore, the median AUC of CDHP was significantly higher in patients 75 years or older than in those younger than 75 years (P = 0.004). This effect was caused by reduced renal function in the elderly, because CDHP is excreted in the urine by glomerular filtration. The opposing effects of aging on the oral clearance of tegafur and the AUC of CDHP may offset each other, leading to unchanged systemic exposure of 5-FU.

  T Watanabe , K Maeda , T Kondo , H Nakayama , S Horita , H Kusuhara and Y. Sugiyama
 

The clearance route and the absolute values for hepatic and renal clearance of drugs are important criteria for the selection of drug candidates. Based on pharmacokinetic theory, by assuming that uptake is the rate-determining process for the biliary excretion of drugs, organ intrinsic clearance should be simply estimated by the intrinsic uptake. In this study, to investigate whether organ clearance can be predicted from the in vitro uptake activity, we performed uptake experiments using isolated hepatocytes and kidney slices, integration plot analyses, and in vivo pharmacokinetic studies using 12 barely metabolized drugs in rats. The in vivo hepatic and renal clearance could be approximated by uptake clearance estimated from integration plot analyses, except for the renal clearance of some drugs that was relatively small. The comparison of intrinsic uptake clearance from in vitro experiments and integration plot studies revealed that in vivo hepatic uptake was well explained by uptake into isolated hepatocytes, whereas in kidney, in vivo uptake clearance was 10 to 100 times that in kidney slices and a scaling factor is required for its prediction from in vitro experiments. The organ clearance and the fraction excreted into urine could be predicted from in vitro studies except for drugs whose renal clearance was relatively small. This study suggests that the uptake process is the determining factor for organ clearance of minimally metabolized drugs, and uptake assays using isolated hepatocytes and kidney slices are useful for evaluating the uptake clearance.

  K Fujita , H Nakayama , W Ichikawa , W Yamamoto , H Endo , F Nagashima , R Tanaka , T Miya , Y Sunakawa , K Yamashita , K Mizuno , H Ishida , K Araki , M Narabayashi , K Miwa , Y Ando , Y Akiyama , K Kawara , T Hirose and Y. Sasaki
 

S-1 is an oral anticancer agent that combines tegafur, a prodrug of 5-fluorouracil (5-FU), and 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase. We examined the effects of aging on the pharmacokinetics of the components of S-1. The median area under the concentration-time curve (AUC) of active 5-FU did not significantly differ between 10 patients 75 years or older and 53 patients younger than 75 years (P = 0.598, Mann-Whitney U test). It is interesting to note that the median oral clearance of tegafur in patients 75 years or older was significantly lower than that in patients younger than 75 years (P = 0.011). Furthermore, the median AUC of CDHP was significantly higher in patients 75 years or older than in those younger than 75 years (P = 0.004). This effect was caused by reduced renal function in the elderly, because CDHP is excreted in the urine by glomerular filtration. The opposing effects of aging on the oral clearance of tegafur and the AUC of CDHP may offset each other, leading to unchanged systemic exposure of 5-FU.

  T Watanabe , K Maeda , T Kondo , H Nakayama , S Horita , H Kusuhara and Y. Sugiyama
 

The clearance route and the absolute values for hepatic and renal clearance of drugs are important criteria for the selection of drug candidates. Based on pharmacokinetic theory, by assuming that uptake is the rate-determining process for the biliary excretion of drugs, organ intrinsic clearance should be simply estimated by the intrinsic uptake. In this study, to investigate whether organ clearance can be predicted from the in vitro uptake activity, we performed uptake experiments using isolated hepatocytes and kidney slices, integration plot analyses, and in vivo pharmacokinetic studies using 12 barely metabolized drugs in rats. The in vivo hepatic and renal clearance could be approximated by uptake clearance estimated from integration plot analyses, except for the renal clearance of some drugs that was relatively small. The comparison of intrinsic uptake clearance from in vitro experiments and integration plot studies revealed that in vivo hepatic uptake was well explained by uptake into isolated hepatocytes, whereas in kidney, in vivo uptake clearance was 10 to 100 times that in kidney slices and a scaling factor is required for its prediction from in vitro experiments. The organ clearance and the fraction excreted into urine could be predicted from in vitro studies except for drugs whose renal clearance was relatively small. This study suggests that the uptake process is the determining factor for organ clearance of minimally metabolized drugs, and uptake assays using isolated hepatocytes and kidney slices are useful for evaluating the uptake clearance.

  K Teshima , R Murakami , E Tomitaka , T Nomura , R Toya , A Hiraki , H Nakayama , T Hirai , M Shinohara , N Oya and Y. Yamashita
  Objective

To evaluate whether saliva production reflects the parotid volume during the course of radiation therapy (RT) in patients with head-and-neck cancer.

Methods

Twenty patients with advanced oral squamous cell carcinomas, who were treated with preoperative chemo-RT, underwent morphological assessment with CT or MRI and functional assessment with the Saxon test. For the Saxon test, saliva production was measured by weighing a gauze pad before and 2 min after chewing without swallowing; the low-normal value is 2 g. Saliva production and parotid volumes before and 2 weeks after RT were compared with the paired t-test, the Spearman rank correlation test and the Fisher exact test.

Results

After 30 Gy irradiation, mean saliva production was decreased from 4.2 to 1.0 g (P < 0.01); the reduction in saliva production ranged from 1.7 to 5.4 g (mean 3.2 g). The mean parotid volume was decreased from 68.2 to 47.9 cm3 (P < 0.01); the post-RT:pre-RT parotid volume ratio ranged from 54% to 85% (mean 71%). Although the initial parotid `volume was correlated with initial saliva production (r = 0.47, P = 0.04), no significant correlation was noted after RT (r = 0.08, P = 0.71), and there were considerable individual variations. The parotid volume ratio was inversely correlated with the saliva-reduction amount (r = – 0.79, P < 0.01).

Conclusions

There was a correlation between decreased parotid gland volume and decreased saliva production in patients with head-and-neck cancer undergoing RT. Parotid volume reduction may predict parotid gland function.

  H Ajima , H Ogata , K. i Fujita , K Miwa , Y Sunakawa , K Mizuno , H Ishida , K Yamashita , H Nakayama , K Kawara , H Takahashi and Y. Sasaki
  Objective

Recently, significant progress in treatment of metastatic colorectal cancer has been achieved. Either FOLFIRI (fluorouracil, leucovorin and irinotecan) or modified FOLFOX6 (fluorouracil, leucovorin and oxaliplatin, oxaliplatin dose 85 mg/m2) is selected as first-line therapy in clinical practice in Japan. However, economic burden of colorectal cancer is considerable.

Methods

Analysis was made for all patients who were treated with FOLFIRI or modified FOLFOX6 for metastatic colorectal cancer. Regimen of FOLFIRI was compared with modified FOLFOX6 under consideration from clinical and economic standpoints. Progression free survival, response, toxicity and cancer care cost in patients with metastatic colorectal cancer was analyzed. Direct costs based on the fee schedule of the Japanese national health insurance were calculated.

Results

Median progression free survival was 7.7 months for FOLFIRI versus 8.4 months for modified FOLFOX6 (P = 0.48). Overall cost for first four cycles was ¥756 284 for FOLFIRI and ¥1 081 162 for modified FOLFOX6 (P < 0.0001). All grade alopecia was significantly more frequent with FOLFIRI than with modified FOLFOX6 (P = 0.04). All grade neuropathy was more observed with modified FOLFOX6 than FOLFIRI (P = 0.0002).

Conclusions

FOLFIRI is inexpensive in the initial stage of treatment which a number of patients can receive chemotherapy than modified FOLFOX6 as first-line therapy for metastatic colorectal cancer in Japanese national insurance system.

  K Kodama , H Nakayama , K Sakamoto , S Fukuzawa , T Kigawa , T Yabuki , M Kitabatake , K Takio and S. Yokoyama
 

A variety of unique codons have been employed to expand the genetic code. The use of the opal (UGA) codon is promising, but insufficient information is available about the UGA suppression approach, which facilitates the incorporation of non-natural amino acids through suppression of the UGA codon. In this study, the UGA codon was used to incorporate 4-iodo-l-phenylalanine into position 32 of the Ras protein in an Escherichia coli cell-free translation system. The undesired incorporation of tryptophan in response to the UGA codon was completely repressed by the addition of indolmycin. The minor amount (3%) of contaminating 4-bromo-l-phenylalanine in the building block 4-iodo-l-phenylalanine led to the significant incorporation of 4-bromo-l-phenylalanine (21%), and this problem was solved by using a purified 4-iodo-l-phenylalanine sample. Optimization of the incubation time was also important, since the undesired incorporation of free phenylalanine increased during the cell-free translation reaction. The 4-iodo-l-phenylalanine residue can be used for the chemoselective modification of proteins. This method will contribute to advancements in protein engineering studies with non-natural amino acid substitutions.

 
 
 
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