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K Hatakeyama

Publications and source records attributed to K Hatakeyama.

At least 19 recordsLinked to original sources
PubMed1992

IMP dehydrogenase inhibitors reduce intracellular tetrahydrobiopterin levels through reduction of intracellular GTP levels. Indications of the regulation of GTP cyclohydrolase I activity by restriction of GTP availability in the cells.

GTP cyclohydrolase I exhibits a positive homotropic cooperative binding to GTP, which raises the possibility of a role for GTP in regulating the enzyme reaction (Hatakeyama, K., Harada, T., Suzuki, S., Watanabe, Y., and Kagamiyama, H. (1989) J. Biol. Chem. 264, 21660-21664). We examined whether or not the intracellular GTP level is within the range of affecting GTP cyclohydrolase I activity, using PC-12 rat pheochromocytoma and IMR-32 human neuroblastoma cells. Since GTP cyclohydrolase I was the rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin in these cell lines, the intracellular activities of this enzyme were reflected in the tetrahydrobiopterin contents. We found that the addition of guanine or guanosine increased GTP but not tetrahydrobiopterin in these cells. On the other hand, three IMP dehydrogenase inhibitors, tiazofurin, 2-amino-1,3,4-thiadiazole, and mycophenolic acid, decreased both GTP and tetrahydrobiopterin in a parallel and dose-dependent manner, and these effects were reversed by the simultaneous addition of guanine or guanosine. There was no evidence suggesting that these inhibitors inhibited other enzymes involved in the biosynthesis and regeneration of tetrahydrobiopterin. Comparing intracellular activities of GTP cyclohydrolase I in the inhibitor-treated cells with its substrate-velocity curve, we estimated that the intracellular concentration of free GTP is 150 microM at which point the activity of GTP cyclohydrolase I is elicited at its maximum velocity. Below this GTP concentration, GTP cyclohydrolase I activity is rapidly decreased. Therefore GTP can be a regulator for tetrahydrobiopterin biosynthesis.

Animals↗
PubMed1992

Evaluation of the holoenzyme content of aromatic L-amino acid decarboxylase in brain and liver tissues.

We have re-evaluated the content of the holo-form of aromatic L-amino acid decarboxylase in rat tissues. Aromatic L-amino acid decarboxylase was found to consume pyridoxal 5'-phosphate while it underwent decarboxylation-dependent transamination as a side reaction. We observed that the total dopamine formation was proportional to the amount of holoenzyme. Dopamine formation in a tissue extract, which was preincubated with pyridoxal 5'-phosphate, was compared with the same tissue sample but which was prepared without preincubation. Percentages of holo-form of aromatic L-amino acid decarboxylase obtained from such comparison were 78% for brain and 94% for liver tissues. These values were significantly higher than those reported earlier in which the decarboxylation-dependent transamination of the decarboxylase had been overlooked.

Animals↗
PubMed1992

Control of cell-cycle-associated tetrahydrobiopterin synthesis in rat thymocytes.

The cell-cycle progression of rat thymocytes from G0 through G1 to DNA synthesis is associated with a transient synthesis of H4biopterin, the concentration of which reaches a maximum at the time of S-phase entry and then decreases. This synthesis of H4biopterin is controlled by the specific activity of GTP cyclohydrolase I, which peaks in G1/S cells. In contrast, the catalytic activity of sepiapterin reductase remains constant throughout the cell-cycle. At G0 the steady state mRNA levels specific for GTP cyclohydrolase I and sepiapterin reductase, respectively, are below the limits of detection. Both accumulate as the thymocytes progress through the cell-cycle but lack cyclic down regulation. The data indicate that the variations in H4biopterin synthesis during the cell-cycle are caused by growth regulated increase in GTP cyclohydrolase I mRNA expression, with subsequent post-translational inactivation. This latter is likely due to the degree of enzyme phosphorylation.

Alcohol Oxidoreductases↗
PubMed1992

Contribution of the endothelium to intimal thickening in normocholesterolemic and hypercholesterolemic rabbits.

Endothelial cell injury is considered to be a primary event in the pathogenesis of atherosclerosis. In this study, we investigated the aortic intimal lesion after balloon catheterization in hypercholesterolemic and normocholesterolemic rabbits with or without probucol, an antioxidant. After deendothelialization, the rabbits were divided into four groups: 1) a control group fed a standard diet; 2) a probucol-treated group; 3) a cholesterol-fed group; and 4) a group fed a mixed cholesterol and probucol diet. Four animals from each group were killed at 2, 4, and 8 weeks after deendothelialization. The aortic segments of nonendothelialized areas, borderline areas, and uninjured areas were histologically and immunohistochemically examined. Deendothelialized areas showed various degrees of intimal thickening, which was mainly composed of smooth muscle cells in rabbits from groups 1 and 2. The intimal thickness of group 3 was significantly larger than that of other groups in any area examined. The intimal thickness of group 4 was less than that of group 3 despite the hypercholesterolemic state in the former group. The intima of borderline areas was generally thicker than that of nonendothelialized areas. Although the borderline lesions of groups 3 and 4 contained numerous macrophages, the number of macrophages was lower in the nonendothelialized compared with the reendothelized lesion. These data indicate that endothelial cell injuries can cause intimal thickening. The regenerated endothelial covering is favorable for monocyte migration and attachment. This process, together with the proliferation of smooth muscle cells, greatly contributes to the progression of atherosclerosis, which appears to involve lipid oxidation. Probucol prevented intimal thickening to a certain degree in this experiment in the normocholesterolemic as well as the hypercholesterolemic state.

Animals↗
PubMed1992

[Supralevator pelvic exenteration with simultaneous bowel and urinary reconstruction. Two case reports].

Two male patients underwent supralevator pelvic exenteration, preserving their normal voiding and evacuating function. Case 1 was a 19-year-old man with pineal region tumor, and a metastatic lesion in the bottom of the rectovesical pouch, possibly through the ventriculo-peritoneal shunt. Following supralevator pelvic exenteration, the construction of double pouches, a colonic J pouch and Mainz pouch to the urethra, were performed. Case 2 was a 39-year-old man with bulky retrovesical tumor. He underwent supralevator pelvic exenteration by sigmoid colo-proctostomy and U-pouch to the urethra. Both patients achieved continent except for urinary leakage at night and were able to defecate and urinate voluntarily. Urodynamic study revealed that the pressure in their urinary pouches was low.

Adult↗
PubMed1992

[Bacteriological, pharmacokinetic and clinical studies of 5% and 10% granules of cefdinir in the pediatric field].

Bacteriological, pharmacokinetic and clinical studies on cefdinir (CFDN, FK482), a new oral cephalosporin, 5% and 10% granules, were performed in the field of pediatrics. The results are summarized below. 1. Antibacterial activities Antibacterial activities of CFDN against Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, Escherichia coli and Klebsiella pneumoniae were studied in comparison with those of cefaclor (CCL), cefixime (CFIX) and amoxicillin (AMPC). MIC80's of CFDN against S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, B. catarrhalis, K. pneumoniae and E. coli were 0.78, 0.20, less than or equal to 0.025, 0.39, 0.10, 0.20 and 0.10 micrograms/ml, respectively. These results show that CFDN has high antibacterial activities against these organisms. MIC80's of CFDN against Gram-positive bacteria were similar to those of AMPC, and was lower than those of CCL and CFIX. As for antibacterial activities against Gram-negative bacteria (GNB), the MIC80 of CFIX against H. influenzae was 0.05 micrograms/ml, which was slightly lower than that of CFDN. THe MIC80's of CFDN against other GNB were similar to those of CFIX. 2. Absorption and excretion Blood concentrations and urinary excretion rates of CFDN 5% and 10% granules and 100 mg capsule were determined. The data on CFDN 10% granules were similar to those on CFDN 5% granules. At a dose of 3 mg/kg, peak blood concentrations (Cmax's) of CFDN ranged from 0.20 to 2.12 micrograms/ml with 5% granules and from 0.50 to 1.15 micrograms/ml with 10% granules at 2 to 3 hours after dosing. At a dose of 6 mg/kg, peak concentrations were 0.66-2.06 micrograms/ml and 0.70-1.52 micrograms/ml with 5% granules and with 10% granules, respectively. At 8 hours after dosing, blood concentrations were 0.04-0.54 micrograms/ml at 3 mg/kg and 0.06-0.27 micrograms/ml at 6 mg/kg. Blood half-lives were 1.33-4.36 hours at 3 mg/kg and 1.14-3.27 hours at 6 mg/kg. AUC's were 1.7-11.0 micrograms.hr/ml with 3 mg/kg and 2.4-8.7 micrograms.hr/ml with 6 mg/kg. With administration of single 100 mg capsule, Cmax's, blood concentrations after 8 hours, T1/2's and AUC's were 0.79-1.88 micrograms/ml, 0.20 micrograms/ml, 1.54-2.72 hours, and 5.2 micrograms.hr/ml, respectively. Urinary recovery rates in the first 8 hours ranged from 6.85 to 39.2% with 3 mg/kg and 6.08-25.5% with 6 mg/kg.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1992

[Pharmacokinetic and clinical studies on panipenem/betamipron in the pediatric field].

UNLABELLED: Panipenem/betamipron (PAPM/BP), one of the carbapenems, was studied for its absorption and excretion, and clinical efficacy. The following is a summary of the results: 1. Absorption and excretion: Fourteen patients with their ages between 2 years and 14 years were administered with PAPM/BP 10 mg/kg, 20 mg/kg or 30 mg/kg, in 30-minute intravenous drip infusion. Maximum serum levels of PAPM, at dose levels of 10 mg/10 mg/kg, 20 mg/20 mg/kg and 30 mg/30 mg/kg of PAPM/BP, were 27.37 micrograms/ml, 59.3 micrograms/ml, 91.7 micrograms/ml, respectively, at the end of infusion. The half-lives of the 3 dose levels were all within 0.90-0.96 hour. Mean peak serum levels of BP, at dose levels of 10 mg/10 mg/kg, 20 mg/20 mg/kg and 30 mg/30 mg/kg, were 21.77 micrograms/ml, 35.29 micrograms/ml, 50.08 micrograms/ml, respectively, with half-lives of 0.55-0.63 hour. Urinary recovery rates of PAPM in the first 8 hours after administration at dose levels of 10 mg/10 mg/kg, 20 mg/20 mg/kg and 30 mg/30 mg/kg, were 15.9-31.1%, 15.3-36.9%, 11.0-40.5%, respectively, and those of BP during the same time were 33.1-79.1%, 41.3-93.4%, 12.9-94.4%, respectively. 2. CLINICAL RESULTS: Thirty-nine patients, including 2 with purulent meningitis, 1 with septicemia (suspect), 18 with acute pneumonia, 5 with bronchiolitis, 2 with tonsillitis (unable to receive oral antibiotics), 3 with cervical purulent lymphadenitis, 2 with bacterial enteritis, 6 with urinary tract infections were treated with PAPM/BP at dose levels of 30-100 mg/kg/day. Clinical responses in the patients were excellent or good. Even 2 patients with purulent meningitis were treated with PAPM/BP at dose levels of no less than 20 mg/kg x 3 and 33 mg/kg x 3. Most of respiratory and urinary tract infection cases of moderate severities were treated at dose levels of 30-60 mg/kg/day, i.e., 10 mg/kg x 3 or 20 mg/kg x 3. No adverse reaction was observed. One patient suffered from frequent watery diarrhea but the drug was continued to be administered and the patient recovered quickly. Abnormal laboratory findings were noted, in 2 cases with elevation of platelet, in 1 case with elevation of GOT, in 1 case with elevation of monocyte, in 1 with eosinophilia, in 1 with eosinophilia and decrease in platelet count, in 1 with eosinophilia and elevation of GOT and in 2 with elevation of GOT and GPT, but these abnormalities in the 9 cases were slight and transient.

Adolescent↗
PubMed1992

[Pharmacokinetic and clinical studies on meropenem].

Pharmacokinetic and clinical studies on meropenem (MEPM, SM-7338), a new developed carbapenem, were performed and the following results were obtained. 1. Absorption/excretion: Pharmacokinetics of MEPM was studied in 9 children using doses of 10 mg/kg and 20 mg/kg by a 30 minute-drip infusion. Peak plasma levels and plasma half-lives of the 2 doses were 28.4 and 43.0 micrograms/ml, and 0.70 and 0.80 hours, respectively. Their urinary recovery rates were 42.5 to 67.6% and 29.9 to 62.6%, respectively. Cerebrospinal fluid levels and penetration rates of MEPM in a patient with purulent meningitis were 0.66 to 4.01 micrograms/ml and 1.6 to 12.2%, respectively. 2. Clinical study: Forty-nine patients were treated with MEPM at doses exceeding 100 mg/kg/day with purulent meningitis and 30 to 60 mg/kg/day with other infections. MEPM gave "excellent" or "good" responses in 48 cases, an efficacy rate of 98.0%. Only one patient with subdural abscess showed fair response. Diarrhea and rash were observed in 1 case each. Abnormal laboratory test results were noted in 5 patients including elevation of GOT, GPT and eosinophils. In no cases the treatment had to be discontinued.

Absorption↗
PubMed1991

Purification and cDNA cloning of rat 6-pyruvoyl-tetrahydropterin synthase.

6-Pyruvoyl-tetrahydropterin synthase, which catalyzes the second step in the biosynthesis of tetrahydrobiopterin, was purified approximately 18,000-fold to apparent homogeneity from rat liver. The molecular mass of the native enzyme was estimated to be 83 kDa by gel filtration. The enzyme showed a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis corresponding to a molecular mass of 17 kDa. Up to 24 residues of the NH2-terminal sequence were determined by Edman degradation, which released a single amino acid at each step. These results indicate that the enzyme consists of identical subunits. The purified enzyme was digested with lysyl endopeptidase or V8 protease, and 11 peptide fragments were isolated. On the basis of the sequences of these peptides, oligonucleotides were synthesized and used to screen a rat liver cDNA library, and one cDNA clone was isolated. The complete nucleotide sequence of the 1176-base pair cDNA was then determined. The deduced amino acid sequence contained 144 amino acid residues, but a NH2-terminal four-amino acid sequence was not found in the purified protein. Therefore, the mature protein consists of 140 amino acids. A single mRNA band of 1.3 kilobases was obtained by RNA blot analysis of rat liver. The predicted amino acid sequence of 6-pyruvoyl-tetrahydropterin synthase was compared with the Protein Sequence Database of the National Biomedical Research Foundation, revealing significant local similarity to large T antigens from the polyomavirus family.

Alcohol Oxidoreductases↗
PubMed1991

A correlation between GM-CSF gene expression and metastases in murine tumors.

Using 14 transplantable murine tumors, we investigated a possible correlation between their ability to produce the cytokine GM-CSF and the spontaneous metastatic potential when mice were subcutaneously inoculated. The following results were obtained: (1) seven tumors, which produced severe pulmonary metastases and metastatic swelling of lymph nodes, exhibited the ability to produce GM-CSF activity in culture. The cell population analysis revealed that the cells producing GM-CSF were tumor cells themselves, but that contaminating macrophages/granulocytes and T lymphocytes did not produce GM-CSF. The mRNA for GM-CSF was also found in all of these highly metastatic tumors tested. In mice inoculated with a highly metastatic tumor, the GM-CSF mRNA was also found in lungs; (2) in 3 other tumors, which produced histological but not macroscopical pulmonary metastases, no GM-CSF activity could be detected in the culture fluids. GM-CSF mRNA was, however, detected in the tumor cells in the presence of an mRNA-stabilizing agent, cycloheximide, suggesting the possibility that the tumor cells of this type were transcribing GM-CSF gene, and secreting it in undetectable levels; (3) in culture of the 4 remaining poorly or non-metastatic tumors, neither CSF activity nor GM-CSF mRNA could be detected even in the presence of cycloheximide. GM-CSF mRNA was also not found in lungs of tumor-bearing mice. Our results indicate that there may be a correlation between GM-CSF gene expression in tumor cells and spontaneous metastases.

Animals↗
PubMed1991

Cloning and sequencing of cDNA encoding rat GTP cyclohydrolase I. The first enzyme of the tetrahydrobiopterin biosynthetic pathway.

A full-length cDNA clone for GTP cyclohydrolase I, the first enzyme of the tetrahydrobiopterin biosynthetic pathway, was isolated and characterized. Synthetic oligonucleotides, constructed according to selected amino acid sequences of purified GTP cyclohydrolase I, were used to screen a rat liver cDNA library. Four clones were isolated, and the length of the longest cDNA insert was 1024 base pairs. The identity of the cDNA was confirmed by amino acid sequence data for eight fragments obtained by lysyl endopeptidase digestion of the purified protein. The coding region encoded a protein of 241 amino acid residues, but the NH2 terminus of the protein contained 11 additional amino acid residues not present in the purified protein. RNA blot analysis showed a single mRNA species of 1.2 kilobases in rat liver. A characteristic feature of the deduced amino acid sequence of GTP cyclohydrolase I was the presence of sequences similar to those proposed for the phosphorylation sites for casein kinase II and growth-associated histone H1 kinase. Furthermore, significant similarity was found to the highly conserved sequences of dihydrofolate reductases, which are known to be involved in the binding of the pterin group of dihydrofolate to the reductases. This region in GTP cyclohydrolase I may be assigned to the binding site of tetrahydrobiopterin, one of the inhibitors of this enzyme.

Amino Acid Sequence↗
PubMed1991

Supralevator pelvic exenteration with colonic J-pouch-anal anastomosis and Mainz pouch operation with anastomosis to the urethra. Report of a case.

This is the first documented case report in which construction of double pouches, a colonic J-pouch and a Mainz pouch with anastomosis to the urethra, was performed in a patient who underwent supralevator pelvic exenteration. We have shown that the operation is feasible; the patient was continent, except for nightly urinary leakage, and was able to defecate and urinate spontaneously without any catheterization. Based on the experience of this case, we believe that this combined operation results in a better quality of life for the patient because of the avoidance of both urinary and fecal stomas. If justified pathologically, this operation may represent an improvement for those patients with extensive cancer of the rectum, which invades the adjacent anterior viscera, or that of the bladder, which invades the posterior viscera.

Adult↗
PubMed1991

A new rat colon cancer cell line metastasizes spontaneously: biologic characteristics and chemotherapeutic response.

A new cell line (RCN-9) was established in culture from a transplantable rat colon adenocarcinoma, which was induced in the colon of a male Fischer F344 rat by subcutaneous administration of 1,2-dimethylhydrazine. When RCN-9 cells were injected subcutaneously or into the cecal subserosa of syngeneic rats, carcinomas with progressive growth were obtained and the development of lung (63.6%) and liver (40.0%) metastases, respectively, ensued. Antitumor effects of 5-fluorouracil (5-FU), adriamycin (ADM) and mitomycin C (MMC) against RCN-9 were examined in vivo and in vitro. 5-FU and ADM had antitumor effects both in vivo and in vitro; MMC had antitumor effects in vitro. These results show that the RCN-9 cell line can be used both as a model to study mechanisms of metastasis from colon carcinoma and as a model in chemotherapeutic studies of metastatic disease from colon carcinoma.

Adenocarcinoma↗
PubMed1991

Gastric bleeding and increased gastric vascular permeability induced by platelet activating factor (PAF): effect of drugs that affect arachidonate metabolism.

The injurious effect of platelet activating factor (PAF) on gastric mucosa was studied by measuring bleeding in the acid perfused stomach of anesthetized rats. The effect of PAF on gastric mucosal vascular permeability (GMVP) was assessed by dye-leakage in the saline perfused stomach of anesthetized rats. Intravenous infusion of PAF (100 ng/kg/min for 20 min) apparently caused gastric bleeding under the gastric luminal perfusion with 150 mM HCl solution,, with the peak response at 50-70 min; biopsy indicated the presence of mucosal lesions. GMVP was markedly increased with the peak response at 20-40 min. Pretreatment with CV-3988 (1 or 10 mg/kg, i.v.), a PAF antagonist, dose-dependently blocked the PAF-induced gastric bleeding and increase in GMVP. Pretreatment with hydrocortisone acetate (20 or 40 mg/kg, s.c.) reduced PAF-induced gastric bleeding and increase in GMVP, in contrast to the aggravation by caffeic acid (1 or 5 mg/kg, s.c.). Indomethacin (1 or 5 mg/kg, s.c.) prevented PAF-induced gastric bleeding, and it depressed the increase in GMVP in the case of the lower dose. Prostaglandin E2 (50 or 500 micrograms/kg, s.c.) significantly reduced PAF-induced gastric bleeding, but had little effect on PAF-induced increase in GMVP. 1-Benzylimidazole (10 or 50 mg/kg, s.c.) also inhibited PAF-induced gastric bleeding and depressed the increase in GMVP at the higher dose. These results suggest that increased GMVP plays a significant role in producing the gastric damage by PAF. Changes in the mucosal level of cyclooxygenase products, especially thromboxanes, by drugs modifying the arachidonate metabolism would be closely associated with their prevention or aggravation of gastric damage induced by PAF.

Animals↗
PubMed1991

[Multiple sclerosis with higher cerebral dysfunction: a case report].

Higher cerebral dysfunctions such as aphasia, apraxia and agnosia have seldom been reported in multiple sclerosis (MS). 12 year-old right-handed boy felt unsteadiness of the body and headache for several days. Two months later, he had the same episode and complained of visual disturbance, and weakness and sensory disturbance on the face and the extremities. Additionally, he showed amnestic aphasia, acalculia, ideomotor apraxia, finger agnosia and right-left disorientation. Cerebrospinal fluid examinations revealed increases IgG, myelin basic protein and neuron specific enolase (11%, 25 ng/ml and 28.8 ng/ml, respectively). X-ray CT scan and MRI-CT examinations revealed sclerotic lesions on the left parietal white matter and the right mid-brain. The diagnosis was made as MS. He was treated with m-PSL (methyl-prednisolone) pulse therapy for three weeks and consecutively treated with PSL for four weeks. He recovered gradually, but visual disturbance and facial palsy remained. After seven months MRI-CT showed a high signal intensity on the left parietal white matter in spite of the disappearance of the lesion on X-ray CT scan. We suggest that these higher cerebral dysfunctions may result from the lesion of the left parietal white matter which produces a disconnection between each cortical area.

Agnosia↗
PubMed1991

[The usefulness of nucleolar organizer regions in diagnosis of colonic epithelial neoplasia].

The Ag-NORs technique, staining nucleolar organizer regions, was performed on 23 areas of colonic normal mucosa, 17 adenomas with low grade atypical and 8 adenocarcinoma invading submucosa, to examine its possibility of application to the pathological diagnosis of colonic epithelial neoplasia. In normal colonic gland, the average number of Ag-NORs per 1 nucleus in cells of lower two-thirds showed significantly higher value (p less than 0.01) than higher one-third, and the mean cross-section area per 1 Ag-NOR in lower two-thirds showed a tendency to be larger than higher one-third. This results suggested that there was a positive correlation between the proliferative activity of cells and the number and size of Ag-NORs. A comparison of normal gland, adenoma and adenocarcinoma showed that the mean cross-section area of Ag-NORs correlated positively to their histological grade of atypia, but the average number did not. However using these two parameters, these three lesions had a tendency to be discriminated respectively at the average Ag-NORs number of 2.8 dots and the area of 2 microns. These results suggested that the Ag-NORs technique was expected to be a useful method for histopathological diagnosis of colonic epithelial neoplasia.

Adenocarcinoma↗