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Biomedical subjects

H Fujino

Publications and source records attributed to H Fujino.

At least 19 recordsLinked to original sources
PubMed2007

CYP2C76-mediated species difference in drug metabolism: a comparison of pitavastatin metabolism between monkeys and humans.

The monkey is often used to predict metabolism of drugs in humans since it generally shows a metabolic pattern similar to humans. However, metabolic profiles different from humans are occasionally seen in monkeys for some drugs including pitavastatin. Recently, we have successfully identified a monkey-specific cytochrome P450 (CYP) 2C76, which possibly accounts for a species difference between monkeys and humans because of its sequence and functional uniqueness. The present study on the role of CYP2C76 and other monkey CYP2Cs in pitavastatin metabolism, as an example, has revealed that CYP2C76 is important for the metabolism of the lactone form, indicating a major role of CYP2C76 for the difference in the metabolism of pitavastatin and possibly other drugs between monkeys and humans. The current investigation on the involvement of CYP2C76 in the metabolism of other drugs is expected to reveal further the further importance of this monkey-specific drug-metabolizing enzyme.

Animals↗
PubMed2006

Prediction of gait outcome with the knee-ankle-foot orthosis with medial hip joint in patients with spinal cord injuries: a study using recursive partitioning analysis.

STUDY DESIGN: Retrospective study of the degree of gait independence achieved by persons with spinal cord injury (SCI) using knee-ankle-foot orthosis with a medial single hip joint (MSH-KAFO). OBJECTIVE: To examine the effects of the neurological level, degree of paresis, age, and inhibitory physical/other factors on the gait with a MSH-KAFO in patients with SCIs. SETTING: Three university hospitals and two rehabilitation hospitals in Japan. METHODS: The 45 patients (36 men, nine women) examined included 10 with injuries in the cervical cord between C6 and C8 (group C), 20 with injuries in the upper-middle thoracic cord between T4 and T10 (group UT), and 15 with injuries in the lower thoracic-lumbar cord between T12 and L1 (group TL). Mean age was 34.0 years (range 16-68 years). Of these patients, 13 used the Walkabout, four used the gear joint, and 28 used the Primewalk as the medial hip joint. Recursive partitioning, which predicted the final status of gait from the level, degree of paresis, age, and inhibitory factors, was performed, and a decision tree for gait was constructed. Inhibitory factors were spasticity, involuntary spasms or muscle contractions, pain, contracture, weakness of the upper extremities, and decreased motivation to perform gait exercise. The degree of gait independence was rated on the following five-point scale: outdoor independent gait (5 points), indoor independent gait (4 points), indoor supervised gait (3 points), indoor assisted gait (2 points), and gait within parallel bars (1 point). New branches were added to the decision tree for gait based on the clinical experience, thereby constructing a new decision tree. RESULTS: The coincident ratio between the value predicted on the basis of the decision tree of gait and the value actually observed was 53.3%. The coincident ratio between the value predicted on the basis of the modified decision tree of gait and the actually observed value was 68.9%. CONCLUSION: The results provide valuable information to medical teams that may assist prescription of gait orthoses.

Adolescent↗
PubMed2006

The balance of VEGF-C and VEGFR-3 mRNA is a predictor of lymph node metastasis in non-small cell lung cancer.

A positive association between vascular endothelial growth factor-C (VEGF-C) expression and lymph node metastasis has been reported in several cancers. However, the relationship of VEGF-C and lymph node metastasis in some cancers, including non-small cell lung cancer (NSCLC), is controversial. We evaluated the VEGF-C and vascular endothelial growth factor receptor-3 (VEGFR-3) expression in NSCLC samples from patients who had undergone surgery between 1998 and 2002 using real-time quantitative RT-PCR and immunohistochemical staining. We failed to find a positive association between VEGF-C and VEGFR-3 mRNA expression and lymph node metastasis in NSCLC. An immunohistological study demonstrated that VEGF-C was expressed not only in cancer cells, but also in macrophages in NSCLC, and that VEGFR-3 was expressed in cancer cells, macrophages, type II pneumocytes and lymph vessels. The VEGF-C/VEGFR-3 ratio of the node-positive group was significantly higher than that of the node-negative group. Immunohistochemical staining showed that VEGFR-3 was mainly expressed in cancer cells. The immunoreactivity of VEGF-C and VEGFR-3 was roughly correlated to the mRNA levels of VEGF-C and VEGFR-3 in real-time PCR. VEGF-C mRNA alone has no positive association with lymph node metastasis in NSCLC. The VEGF-C/VEGFR-3 ratio was positively associated with lymph node metastasis in NSCLC. This suggests that VEGF-C promotes lymph node metastasis while being influenced by the strength of the VEGF-C autocrine loop, and the VEGF-C/VEGFR-3 ratio can be a useful predictor of lymph node metastasis in NSCLC.

Adult↗
PubMed2005

Serious cardiac and pulmonary calcification in a young peritoneal dialysis patient: potential role of continuous correction of acidosis.

We describe a 40-month-old male infant with renal failure, treated with peritoneal dialysis, who developed massive calcification of soft tissues including the heart and lungs with subsequent cardiopulmonary insufficiency. A diagnosis of Jeune syndrome was made. After starting peritoneal dialysis, the patient exhibited an intractable metabolic acidosis of unknown etiology necessitating treatment with intravenous or oral sodium bicarbonate. Myocardial calcification was first detected by 2-dimensional echocardiography performed 3 months after starting dialysis. The patient was not suitable for renal transplantation because of his cardiac dysfunction and died of cardiac and respiratory failure at the age of 6 years. Although the patient exhibited a variety of risk factors for ectopic calcification including hyperphosphatemia, hyperparathyroidism, high calcium-phosphate product and treatment with vitamin D, the early and massive soft tissue calcification may have been accelerated by correction of the metabolic acidosis. Therefore, the use of sodium bicarbonate may be involved in the etiology of the myocardial calcification.

Acidosis↗
PubMed2004

Repeated gamma knife radiosurgery for multiple metastatic brain tumours.

BACKGROUND: The effectiveness of repeated gamma knife radiosurgery (GKS) for the treatment of multiple metastatic brain tumours was evaluated. METHODS: This study included 16 patients with 242 tumours, 10 men and 6 women with a mean age of 60.3 years at initial GKS, who underwent GKS four times or more for newly developed metastatic tumours. FINDINGS: Sixteen patients underwent a total of 83 GKS procedures (range 4 to 8, mean 5.2). The mean number of metastases at each GKS procedure was 2.9 and the number of tumours tended to increase at the 5th GKS procedure compared with the 1st, but not significantly. The mean interval between each procedure was 4.8 months and was not significantly different. Median survival was 22.4 months (range 9.4-78.9 months) and the primary site was not correlated with survival time. The total number of treated tumours tended to correlate to survival time, but not significantly. Use of adjuvant whole brain radiation also had no significant effect on survival time. The Karnofsky performance status was maintained at more than 70 in most patients, but decreased significantly between initial and final GKS. Death due to progression of brain lesions occurred in only about 30% of patients regardless of the multiple newly developed brain metastases. CONCLUSIONS: Repeated radiosurgery for brain metastases is effective and relatively long survival can be expected in some patients associated with a low risk of radiation-induced injury.

Adult↗
PubMed2004

Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice.

We examined the antitumour effect of a combination of betulinic acid (BA) and vincristine (VCR) on murine melanoma B16F10 cells in vitro and in vivo. Betulinic acid, a pentacyclic triterpene, showed a synergistic cytotoxic effect on melanoma cells by combinational use of VCR. Betulinic acid and VCR induced cell cycle arrest at different points (BA at G1 phase and VCR at G2/M phase) and caused apoptosis in B16F10 melanoma cells. In the in vivo study, VCR inhibited metastasis of tumour cells to the lung. The addition of BA to VCR augmented suppression of the experimental lung metastasis of melanoma cells in C57BL/6 mice. The number of lung nodules of more than 1 mm in diameter in mice treated with BA and VCR was less than that in mice treated with VCR alone. These results suggest that BA is an effective supplement for enhancing the chemotherapeutic effect on malignant melanoma.

Animals↗
PubMed2003

Gamma knife radiosurgery for metastatic tumours in the brain stem.

BACKGROUND: Stereotactic radiosurgery has become important in the treatment of metastatic brain tumours and is often the first choice modality for eloquent or deep locations such as the brain stem. This study evaluated the efficacy of gamma knife radiosurgery (GKS) for the treatment of brain stem metastases. METHODS: The medical records of 25 patients with 31 tumours, 11 men and 14 women aged 42 to 78 years (mean 57.1 years), who underwent GKS for metastatic tumours in the brain stem were retrospectively reviewed. The results of GKS were evaluated according to the change in tumour size on neuro-imaging. FINDINGS: The most common location of the primary malignancy was the lung followed by the breast. Adenocarcinoma was found in 19 patients (24 lesions). No case of squamous cell carcinoma was found. The mean calculated tumour volume was 2.1 cm(3) and the mean prescription dose to the tumour margin was 13.0 Gy. Mean duration of neuro-imaging follow up was 5.2 months and the overall tumour control rate was 77.4%. There was a significant correlation between the marginal dose delivered and the effect on neuro-imaging. New radiation-induced injury in the surrounding brain occurred in only 2 patients. INTERPRETATION: GKS for brain stem metastases using a marginal dose of 15 Gy or less is effective and relatively safe. Accurate targeting of the tumour and safe dose planning are essential to obtain satisfactory results with GKS for brain stem metastases.

Adenocarcinoma↗
PubMed2003

Esophageal actinomycosis after allogeneic peripheral blood stem cell transplantation for extranodal natural killer/T cell lymphoma, nasal type.

We report a 19-year-old man with extranodal natural killer (NK)/T cell lymphoma, nasal type treated by allogeneic peripheral blood stem cell transplantation (allo-PBSCT). His lymphoma was chemoresistant, and disseminated during local radiotherapy. The patient received allo-PBSCT from his HLA-1 locus mismatched sister using busulfan (BU), cyclophosphamide (CY) and VP-16 as the conditioning regimen. His course was complicated by esophageal actinomycosis 9 months after transplantation, which resulted in the rupture of the right common carotid artery. These observations suggest that actinomycosis should be monitored carefully after transplantation in patients who have received local radiation therapy before the procedure.

Actinomycosis↗
PubMed2003

Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase: human UDP-glucuronosyltransferase enzymes involved in lactonization.

1. Pitavastatin is a potent competitive inhibitor of HMG-CoA reductase little metabolized in hepatic microsomes. Pitavastatin lactone, which can be converted back to the unchanged form, is the major metabolite of pitavastatin in humans. To clarify the mechanism of the lactonization of pitavastatin and the metabolic properties of the lactone, we performed experiments in vitro. 2. On addition of UDP-glucuronic acid, human hepatic microsomes produced pitavastatin lactone and an unknown metabolite (UM-2). UM-2 was converted to its unchanged form by enzymatic hydrolysis and to a lactone form non-enzymatically. Using several human UGT-expressing microsomes, UGT1A3 and UGT2B7 were principally responsible for glucuronidation of pitavastatin leading to lactonization. 3. No marked difference in intrinsic clearance between pitavastatin and its lactone form was detected in human hepatic microsomes. 4. Pitavastatin lactone showed no inhibitory effects on CYP2C9- and CYP3A4-mediated metabolism of model substrates in contrast to other HMG-CoA reductase inhibitors. 5. The mechanism of pitavastatin lactone formation has been clarified, in that glucuronidation by UGT occurs first followed by lactonization via an elimination reaction. It was also found that pitavastatin lactone demonstrates no drug-drug interactions.

Biotransformation↗
PubMed2003

Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase: similarities and difference in the metabolism of pitavastatin in monkeys and humans.

1. To elucidate any potential species differences, the in vitro metabolism of pitavastatin and its lactone was studied with hepatic and renal microsomes from rats, dogs, rabbits, monkeys and humans. 2. With the addition of UDP-glucuronic acid to hepatic microsomes, pitavastatin lactone was identified as the main metabolite in several animals, including humans. 3. Metabolic clearances of pitavastatin and its lactone in monkey hepatic microsome were much greater than in humans. 4. M4, a metabolite of pitavastatin with a 3-dehydroxy structure, was converted to its lactone form in monkey hepatic microsomes in the presence of UDP-glucuronic acid as well as to pitavastatin. These results implied that lactonization is a common pathway for drugs such as 5-hydroxy pentanoic acid derivatives. 5. The acid forms were metabolized to their lactone forms because of their structural characteristics. 6. UDP-glucuronosyltransferase is the key enzyme responsible for the lactonization of pitavastatin, and overall metabolism is different compared with humans owing to the extensive oxidative metabolism of pitavastatin and its lactone in monkey.

Animals↗
PubMed2001

Simultaneous determination of taxol and its metabolites in microsomal samples by a simple thin-layer chromatography radioactivity assay--inhibitory effect of NK-104, a new inhibitor of HMG-CoA reductase.

The inhibitory effect of NK-104, a potent inhibitor of HMG-CoA reductase, on taxol metabolism was examined using radio-TLC. This method is described for in vitro measurement of taxol metabolites as an alternative to the commonly used HPLC assay. After incubation of 14C-taxol with human liver microsomes, the supernatants were developed using a solvent system consisting of toluene-acetone-formic acid (60:39:1, v/v) and quantified with a bioimaging analyzer. The described method provides a valuable tool for the simultaneous determination of unchanged taxol and its major metabolites. There was no inhibitory effect of NK-104 on CYP-mediated metabolism of taxol in human liver microsomes.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Bernard-Soulier syndrome associated with 22q11.2 microdeletion.

We describe a Japanese girl with Bernard-Soulier syndrome and 22q11.2 microdeletion. She had viral infections and recurrent thrombocytopenia and hemorrhagic diathesis after cardiac surgery. As congenital heart defects and abnormal immunity are the most common clinical manifestations associated with 22q11.2 deletion, patients with this association may have a greater risk of developing a severe bleeding disorder.

Abnormalities, Multiple↗
PubMed2001

FP prostanoid receptor activation of a T-cell factor/beta -catenin signaling pathway.

FP prostanoid receptors are G-protein-coupled receptors (GPCR) that consist of two known isoforms, FP(A) and FP(B). These isoforms, which are generated by alternative mRNA splicing, are identical except for their carboxyl-terminal domains. Previously we have shown that stimulation of both isoforms with prostaglandin F(2alpha) (PGF(2alpha)) activates the small G-protein Rho, leading to morphological changes consisting of cell rounding and the formation of cell aggregates. Following the removal of PGF(2alpha), however, FP(A)-expressing cells show rapid reversal of cell rounding, whereas FP(B)-expressing cells do not. We now show that acute treatment of FP(B)-expressing cells with PGF(2alpha) leads to a subcellular reorganization of beta-catenin, a decrease in the phosphorylation of cytoplasmic beta-catenin, and persistent stimulation of Tcf/Lef-mediated transcriptional activation. This does not occur in FP(A)-expressing cells and may underlie the differences between these isoforms with respect to the reversal of cell rounding. The Tcf/beta-catenin signaling pathway is known to mediate the actions of Wnt acting through the heptahelical receptor, Frizzled, and has not been associated previously with GPCR activation. Our findings expand the signaling possibilities for GPCRs and suggest novel roles for FP receptors in normal tissue development and malignant transformation.

Animals↗
PubMed2001

Virus-associated hemophagocytic syndrome due to rubella virus and varicella-zoster virus dual infection in patient with adult idiopathic thrombocytopenic purpura.

A 26-year-old woman with idiopathic thrombocytopenic purpura (ITP) was admitted to our hospital because of fever and rash. Blood tests revealed thrombocytopenia, liver dysfunction, coagulopathy, and hyperferritinemia. Bone marrow examination revealed many atypical lymphocytes and some histiocytes with hemophagocytosis. On admission she was diagnosed with rubella virus-associated hemophagocytic syndrome (VHAS), but on laboratory examination, she was seropositive for varicella-zoster virus (VZV)-IgM as well as rubella virus-IgM. She was therefore diagnosed with dual infection by rubella virus and VZV. Her simultaneous rubella virus and VZV infection may have been related to the VAHS pathogenesis. She was treated with prednisolone and gamma globulin therapy and recovered completely.

Adult↗
PubMed2001

Primary refractoriness to platelet transfusion caused by Nak(a) antibody alone.

BACKGROUND AND OBJECTIVES: Anti-Nak(a), a platelet-specific antibody, occasionally causes platelet-transfusion refractoriness (PTR) together with human leucocyte antigen (HLA) antibodies. Anti-Nak(a) usually appears after frequent platelet transfusions or pregnancy. We report the first case of PTR caused by anti-Nak(a) alone. MATERIALS AND METHODS: A 19-year-old male patient with testicular tumour showed PTR when receiving his first transfusion of platelets. Screening for platelet antigens and platelet antibodies revealed that he had type I CD36 (Nak(a)) deficiency and that anti-Nak(a), but not anti-HLA, was present before he received his first transfusion. RESULTS: The transfusion of Nak(a)-negative, but HLA non-selected, platelets was effective in raising the platelet count. CONCLUSION: Clinically significant Nak(a) antibody was present as naturally occurring antibody in a platelet glycoprotein IV (CD36)-negative non-transfused male patient.

Adult↗
PubMed2001

Chemotherapy-induced unconjugated hyperbilirubinemia caused by a mutation of the bilirubin uridine-5'-diphosphate-glucuronosyltransferase gene.

Chemotherapy for malignant neoplasms sometimes causes unconjugated hyperbilirubinemia in the absence of liver dysfunction. We analyzed the association of chemotherapy-induced hyperbilirubinemia with mutations of the bilirubin uridine-5'-diphosphate (UDP)-glucuronosyltransferase gene (UGT1A1) from two leukemic patients in whom chemotherapy resulted in a hyperbilirubinemic response. We isolated genomic DNA from peripheral blood samples and amplified UGT1A1 by polymerase chain reaction. The amplified DNA fragments were analyzed by direct sequencing. The genes of the two patients revealed an identical heterozygous missense mutation in exon 1 (211G-->A: G71R). This UGT1A1 mutation may be the basis of chemotherapy-induced unconjugated hyperbilirubinemia.

Adolescent↗