Biomedical subjects

M Fujii

Publications and source records attributed to M Fujii.

At least 289 records · Page 16Linked to original sources

PubMed1998

[Combination chemotherapy with nedaplatin and 5-FU for head and neck cancer].

Nedaplatin (CDGP), which is a CDDP analog, is an effective anticancer agent for head and neck cancer. The first-line chemotherapy for head and neck cancer is reported to be the combination of CDDP and 5-FU. We undertook a clinical trial for combination CDGP and 5-FU to determine whether this chemotherapy has the potential effect of combination with CDDP and 5-FU. First of all, we tried to determine the maximum dose and recommended dose of CDGP in the combination with CDGP and 5-FU by the dose finding regulation method used in combination phase I study. We determined the maximum dose of CDGP as 120 mg/m2, and the recommended dose as 100 mg/m2 with CDGP and 5-FU, 700 mg/m2/day for 5 days. Thirteen cases were treated with CDGP and 5-FU by the recommended dose. Three cases showed CR, and seven cases showed PR. The response rate was 76.9%. Two cases showed hematological toxicity, one grade 3 platelet decreasing and the other grade 3 leucopenia. Two cases showed renal toxicity less than grade 2. Nausea and vomiting were mild. The combination with CDGP and 5-FU seemed to have a strong effect and low toxicity. Further study will be needed to determine the efficacy against head and neck cancer.

Aged↗

PubMed1998

Effects of loxiglumide on pancreatic exocrine secretion stimulated by cholecystokinin-8 in conscious dogs.

The effects of loxiglumide (CAS 107097-80-3, CR 1505), a novel cholecystokinin-A(CCK-A) receptor antagonist, on pancreatic exocrine secretion stimulated by exogenously administered CCK-8 were examined in conscious dogs with chronic pancreatic fistula. Pancreatic exocrine secretion in dogs was significantly increased by intravenous infusion of CCK-8 at a dose of 0.06 microgram/kg/h. Loxiglumide inhibited CCK-8-augmented outputs of pancreatic protein, trypsin and amylase at intravenous doses of 1, 3, 10 mg/kg/h (p < 0.05 or 0.01), and inhibited pancreatic juice volume at a dose of 10 mg/kg/h (p < 0.05). These results demonstrated that the selective CCK-A antagonist loxiglumide inhibited the increase of pancreatic exocrine secretion stimulated by CCK-8 based on selective blockade of receptor binding of CCK in dogs.

Amylases↗

PubMed1998

Effects of loxiglumide on pancreatic exocrine secretion stimulated by meal in conscious dogs.

The effects of loxiglumide (CAS 107097-80-3, CR 1505), a novel cholecystokinin-A(CCK-A) receptor antagonist, on pancreatic exocrine secretion stimulated by meal were examined in conscious dogs with chronic pancreatic fistula. Pancreatic exocrine secretion was stimulated by intraduodenal infusion of a liquid test meal and postprandial plasma CCK levels were apparently elevated. Loxiglumide inhibited the meal-stimulated outputs of pancreatic protein, amylase and bicarbonate at an intravenous dose of 10 mg/kg/h (p < 0.05). However, loxiglumide did not show apparent inhibition of pancreatic juice volume and trypsin output. These results show that the selective CCK-A antagonist loxiglumide may inhibit the increase of pancreatic exocrine secretion based on selective blockade of receptor binding of CCK endogenously induced by meal in dogs.

Amylases↗

PubMed1998

Biochemical and pharmacological profiles of loxiglumide, a novel cholecystokinin-A receptor antagonist.

Loxiglumide ((+/-)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N- pentylglutaramic acid, CAS 107097-80-3, CR1505) is a new derivative of glutaramic acid. Radioligand displacement assay was performed to characterize the selectivity of loxiglumide to CCK-A (cholecystokinin-A) receptor (rat pancreas and bovine gallbladder) and CCK-B/gastrin receptors (guinea pig cerebral cortex and guinea pig gastric parietal cell). And tissue bioassay was performed to investigate the effect of the compound on contractions of the guinea pig gallbladder and ileum. Loxiglumide inhibited 125I-CCK-8 binding to rat pancreatic and bovine gallbladder membranes with IC50 values of 195 and 77.1 nmol/l, respectively. Loxiglumide also inhibited 125I-CCK-8 binding to guinea pig cerebral cortex membranes and parietal cells with IC50 values of 12363 and 15455 nmol/l, respectively. In addition, loxiglumide inhibited 125I-gastrin binding to guinea pig parietal cells with IC50 values of 6134 nmol/l. These results indicate that the affinity of loxiglumide to CCK-A receptor is at least 63 times greater than that to CCK-B/gastrin receptors. In vitro functional studies utilizing CCK-induced contractions of the isolated guinea pig gallbladder and ileum further demonstrate that loxiglumide acts as a competitive CCK antagonist with a high affinity to these tissues (gallbladder, pA2:6.71).

Animals↗

PubMed1998

Effects of loxiglumide on experimental acute pancreatitis in comparison with gabexate mesilate.

Loxiglumide ((+/-)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N- pentylglutaramic acid, CAS 107097-80-3, CR 1505) is a cholecystokinin-A (CCK-A) receptor antagonist. In this report, the effects of loxiglumide and gabexate mesilate were studied on three experimental acute pancreatitis models induced by caerulein, sodium taurocholate + caerulein and closed duodenal loop. The intravenous injection of loxiglumide at 3 and 10 mg/kg (6 times at hourly intervals) significantly inhibited an increase in serum amylase activity induced by the intraperitoneal injection of caerulein (50 micrograms/kg i.p., 6 times at hourly intervals) in mice. But gabexate mesilate at 10, 30 and 60 mg/kg did not. The intravenous infusion of loxiglumide at 18 and 60 mg/kg/h showed a life prolonging effect in the lethal necrotizing pancreatitis, induced by the subcutaneous injection of caerulein (50 micrograms/kg s.c., 4 times at 2 h intervals) after the injection of sodium taurocholate (10%, 0.1 ml/body) into the common bile duct, cumulative survival rates being 86 and 90%, respectively. Gabexate mesilate at 180 mg/kg/h showed the prolonging effect (cumulative survival rates 75%). The intravenous injection of loxiglumide at 6, 18 and 60 mg/kg/h significantly inhibited an increase in total ascitic lipase activity, and plasma amylase and lipase activity of rats with closed duodenal loop. These results suggest that CCK plays an important role in the progression of acute pancreatitis, and that loxiglumide may have a therapeutic potential for pancreatitis.

Acute Disease↗

PubMed1998

[Two patients with obstructive jaundice due to intra-abdominal lymph-node metastases of gastric cancer responding to combination chemotherapy with 5-FU and CDDP].

Combination chemotherapy with 5-FU and CDDP was given to two patients with obstructive jaundice due to intra-abdominal lymph-node metastases of advanced and recurrent gastric cancer. One patient was a primary case associated with lymph-node metastases of portal fissure and periaorta, and the other was a recurrent case associated with lymph-node metastases of hepatoduodenal ligament and periaorta. The regimen consisted of 5-FU 1,000 mg/ m2 (day 1-5, continuous infusion) and CDDP 100 mg/m2 (day 3, 1 hr drip infusion). The interval was from the 6th to 21st day. The response to chemotherapy showed shrinking of intra-abdominal lymph-nodes and reopening of the biliary tract. The patients could be discharged from the hospital without PTBD tube and enjoyed a better quality of life (QOL). This therapy is thought to be effective against obstructive jaundice due to intra-abdominal lymph-node metastases of advanced and recurrent gastric cancer.

Abdomen↗

PubMed1998

Cardiovascular effects of (2RS,3SR)- 2-aminomethyl-2,3,7,8-tetrahydro-2,3,5,8,8-pentamethyl-6H-furo- [2,3-e]indol-7-one hydrochloride (UK-1745), a novel cardiotonic agent with vasodilatory and antiarrhythmic properties.

The cardiovascular effects of (2RS,3SR)-2-aminomethyl-2,3,7,8- tetrahydro-2,3,5,8,8-pentamethyl-6H-furo[2,3-e]indol-7-one hydrochloride (CAS 170684-14-7, UK-1745), a novel cardiotonic agent, were investigated using in vitro and in vivo preparations. In paced left atria isolated from guinea pigs, both UK-1745 and vesnarinone (CAS 81840-15-5) showed a concentration-dependent positive inotropic effect. In spontaneously beating guinea pig right atria, both agents caused only a minimal chronotropic effect. In isolated, blood-perfused canine papillary muscle preparations, UK-1745 and vesnarinone injected intra-arterially into the anterior septal artery (ASA) increased the developed tension in a dose-dependent manner. In isolated, blood-perfused canine sinoatrial node preparations, both agents injected into the right coronary artery (RCA) did not cause any appreciable changes in the sinus rate. UK-1745 increased the blood flow through the ASA and the RCA in a dose-dependent manner, whereas vesnarinone did not. In anesthetized open-chest dogs, UK-1745 injected intravenously increased cardiac contractility and cardiac output, and decreased left ventricular end-diastolic pressure, systemic vascular resistance and heart rate. In experimentally induced acute heart failure in anesthetized open-chest dogs, intravenously injected UK-1745 effectively improved hemodynamic functions. In conscious instrumented dogs, orally administered UK-1745 increased LV dP/dtmax with insignificant changes in systemic blood pressure and heart rate. In mice, orally administered UK-1745 protected the development of ventricular fibrillation induced by chloroform inhalation, whereas vesnarinone did not. Thus, in respect of inotropic and chronotropic effects, UK-1745 closely resembled vesnarinone, but differed from vesnarinone in respect of coronary vasodilating and antiarrhythmic effects. The results suggest that UK-1745 is a novel positive inotropic agent with vasodilatory and antiarrhythmic properties, without significant chronotropic action, and may be beneficial for the treatment of congestive heart failure.

Anesthesia↗

PubMed1998

[Spinal cord stimulation therapy at an early stage for unresponsive patients with hypoxic encephalopathy].

Recently, spinal cord stimulation (SCS) has been used for the treatment of patients in prolonged coma. However, the results of SCS in unresponsive patients with hypoxic encephalopathy at the chronic stage have not been satisfactory. Considering these circumstances, we began SCS from one month after the onset of hypoxic encephalopathy and evaluated its effect. Twelve patients (5 males and 7 females) with hypoxic encephalopathy, ranging in age from 7 to 72 years, were treated with SCS. The causes of hypoxia were acute cardiac failure in 4, automobile exhaust gas poisoning in 2, and asthma, pneumothorax, anaphylaxis, asphyxia, drowning and hypotension during aortic surgery in one patient each. One month after the onset, an electrode for electrical stimulation was implanted in the epidural space at the C2-C4 level under general anesthesia. The spinal cord was stimulated for 8 hours each day, starting on the day after implantation, and was continued for 3 months. Magnetic resonance imaging (MRI), cerebral blood flow (CBF) measurement using xenon-computed tomography (Xe-CT), and measurement of auditory evoked potential (AEP) and somatosensory evoked potential (SEP) were carried out 3 weeks after the onset for presurgical evaluation. Among the 12 patients, 7 (58%) showed clinical improvement, beginning within two weeks after starting stimulation. They were able to communicate with others and to express their emotion. However, disturbance of writing, picture drawing and calculation were not improved by stimulation. From presurgical evaluation, cases in which SCS therapy was effective had the following features: 1) No hemorrhagic infarction in the basal ganglia was demonstrable by MRI. 2) Mean hemispheric CBF measured by the Xe-CT method exceeded 25 ml/100 g per min. 3) The mean increase in hemispheric CBF 20 min after acetazolamide administration exceeded 5 ml/100 g per min. 4) An N20 peak was evident on the median nerve SEP, SCS appears to be an effective supplementary for unresponsive patients with hypoxic encephalopathy at the subacute stage, in addition to rehabilitation and drug therapy.

Adolescent↗

PubMed1998

[A resected case of so-called carcinosarcoma of the lung which was diagnosed as diaphragmatic tumor].

A 64-year-old male complained of right hypochondralgia and was admitted to our hospital. A large tumor (10 x 15 x 10 cm) of the right diaphragm was detected involving the middle and lower lobe of the lung. Microscopic and immunohistochemical examinations showed that bronchiolo-alveolar cell carcinoma was interposed in the sarcoma-like lesion, and this tumor was diagnosed as a so-called carcinosarcoma of the lung.

Carcinosarcoma↗

PubMed1998

[Recent progress of matrix metalloproteinase (MMP) research and its clinical application for cancer therapy].

The matrix metalloproteinases (MMPs) are a family of secreted and membrane-bound zinc-endopeptidases. These enzymes are capable of degrading the extracellular matrix, including collagens, laminin, proteoglycan and fibronectin. In some human cancers, a positive correlation has been demonstrated between MMP expression and the likelihood of developing metastasis. An imbalance between MMPs and the tissues inhibitor of metalloproteinases (TIMPs) may play a significant role in the invasive phenotype of cancers. Although TIMPs have been shown to inhibit tumor metastasis in some in vivo models, they are not suitable for pharmacologic applications due to their short half-life in vivo and large molecular size. In this paper, recent advances in MMP research and reports of clinical applications of synthetic MMP inhibitors for cancer patients are reviewed.

Humans↗

PubMed1997

Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells.

Recently, human interleukin 18 (hIL-18) cDNA was cloned, and the recombinant protein with a tentatively assigned NH2-terminal amino acid sequence was generated. However, natural hIL-18 has not yet been isolated, and its cellular processing is therefore still unclear. To clarify this, we purified natural hIL-18 from the cytosolic extract of monocytic THP.1 cells. Natural hIL-18 exhibited a molecular mass of 18.2 kDa, and the NH2-terminal amino acid was Tyr37. Biological activities of the purified protein were identical to those of recombinant hIL-18 with respect to the enhancement of natural killer cell cytotoxicity and interferon-gamma production by human peripheral blood mononuclear cells. We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. These results suggest that the production and processing of natural hIL-18 are regulated by two processing enzymes, caspase-1 and caspase-3, in THP.1 cells.

Amino Acid Sequence↗

PubMed1997

Analysis of bovine selenoprotein P-like protein gene and availability of metal responsive element (MRE) located in its promoter.

Selenoprotein P-like protein, similar to selenoprotein P, uses multiple TGAs for incorporation of selenocysteines but not as stop codons. It is also characterized by having a His-Pro-rich domain and a regionally differential expression pattern. Hence, in addition to selenium metabolism, this protein is considered to have a developmental function. In the present study, the structure of the selenoprotein P-like protein gene was analyzed. The gene consisted of five exons, and the 5'-flanking region contained a TATA box, TCF-1-CS, bHLH-CS, gamma-IRE-CS, c-Myb-CS, C/EBP-CS, HNF-5-CS, MRE2-CS, etc. The presence of motifs like TCF-1-CS, c-Myb-CS, etc. supports the suggestion that this protein is involved in cellular maturation. Since the presence of MRE2-CS suggests that this protein is related to the antidote effect of selenium against heavy metal intoxication, the availability of this motif was examined using bovine kidney cell lines, CKT-1 and MDBK. Metallothionein mRNA markedly increased 6 h after administration of 10(-6) M CdCl2 and ZnCl2 in both cell lines. No significant alteration was observed in selenoprotein P-like protein mRNA, whereas its basal expression was high, indicating that this protein is constitutively expressed. Thus, it is still possible that this protein acts as an antidote, even though it is not inducible by heavy metals.

Animals↗

PubMed1997

Purification and characterization of the human interleukin-18 receptor.

Interleukin (IL)-18 was identified as a molecule that induces IFN-gamma production and enhances NK cell cytotoxicity. In this paper, we report upon the purification and characterization of human IL-18 receptor (hIL-18R). We selected the Hodgkin's disease cell line, L428, as the most strongly hIL-18R-expressing cell line based on the results of binding assays. This binding was inhibited by IL-18 but not by IL-1beta. The dissociation constant (Kd) of 125I-IL-18 binding to L428 cells was about 18.5 nM, with 18,000 binding sites/cell. After immunizing mice with L428 cells and cloning, a single monoclonal antibody (mAb) against hIL-18R was obtained (mAb 117-10C). Sequentially, hIL-18R was purified from 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS)-extracted L428 cells by wheat germ lectin-Sepharose 4B chromatography and mAb 117-10C-Sepharose chromatography. The internal amino acid sequences of hIL-18R all matched those of human IL-1 receptor-related protein (IL-1Rrp), the ligand of which was unknown to date. When expressed in COS-1 cells, the cDNA of IL-1Rrp conferred IL-18 binding properties on the cells and the capacity for signal transduction. From these results, we conclude that a functional IL-18 receptor component is IL-1Rrp.

Amino Acid Sequence↗

PubMed1997

Cloning and characterization of the 5'-flanking region of the mouse diastrophic dysplasia sulfate transporter gene.

Dyastrophic dysplasia sulfate transporter (DTDST) plays an important role in proteoglycan synthesis in the extracellular matrix of bone and cartilage. Recently, we found that the mouse DTDST gene was induced in pluripotent C3H10T1/2 cells during differentiation by bone morphogenetic protein-2 (BMP-2). To clarify the transcriptional regulation of the DTDST gene, we have cloned the 5'-flanking region of the mouse DTDST gene by the PCR based gene walking method. Sequence analysis revealed the presence of the TATA box followed by GC rich sequences containing two Sp-1 binding sites and a CBFA1 binding site. Transient transfection assays demonstrated that the basal transcriptional activity in osteoblastic MC3T3-E1 cells was mainly present between -309 and -275 bp upstream of the transcription start site (Segment -309/-275) which contained the consensus sequence for the xenobiotic-responsible element (XRE). Nuclear proteins from MC3T3-E1 cells and C3H10T1/2 cells could bind to this short segment in vitro. BMP-2 increased the promoter activity as well as the nuclear protein binding to the sequence in C3H10T1/2 cells. The present data suggest that the DTDST gene expression in osteoblasts and differentiating precursor cells to osteoblast/chondrocyte lineage would be mainly regulated by undetermined XRE binding transcription factors.

Animals↗

PubMed1997

A survey of Salmonella enteritidis in spent hens and its relation to farming style in Hokkaido, Japan.

In order to estimate the distribution of Salmonella including Salmonella enteritidis (SE) and SE-antibodies in commercial layer hen flocks in Hokkaido, the northern prefecture of Japan, a survey of spent layer hens was performed, from August 1996 to January 1997. From the three spent hen processing plants, samples of intestines and sera were collected from 740 birds presented for slaughter from 37 flocks of 22 layer hen farms. Intestines from each birds were cultured for Salmonella including Salmonella enteritidis. Serum from each bird was examined for SE-antibody with the enzyme-linked immunosorbent assay (ELISA). Salmonella (any serotype) and Salmonella enteritidis were isolated from 50 (6.8%) and three (0.4%) of 740 birds, respectively, and SE-antibody positive values were recorded from seven birds (0.9%). SE-antibody positive birds did not always indicate isolation of Salmonella enteritidis, however SE-antibody positive hens were demonstrated only from Salmonella enteritidis positive flocks. Salmonellae were isolated from the birds of ten layer hen farms, all of these hens were raised in houses without windows and with automatic feeders. No isolations of salmonella were made from birds raised in houses with windows. From the windowless houses, Salmonellae were isolated from 46 (21.8%) of 260 birds in houses with four to six cages piled up vertically, and from six (2.5%) of 240 samples from the houses with four to five cages piled in a slanting manner.

Animals↗

PubMed1997

Decrease in amplified telomeric sequences and induction of senescence markers by introduction of human chromosome 7 or its segments in SUSM-1.

Introduction of human chromosome 7 by microcell-mediated chromosome transfer suppresses indefinite division of SUSM-1, an in vitro established human fibroblast line. This cell line has unusually long telomeric sequences although it lacks detectable telomerase activity. Thus, we examined whether such telomeric sequences change upon introduction of chromosome 7 or its segments. In the microcell hybrids that stopped dividing by introduction of chromosome 7, the telomeric sequences were found to be lost or markedly diminished. Introduction of various fragments (2-40 Mb) of chromosome 7 contained in radiation hybrids gave similar results. On the other hand, the telomeric sequences were not altered significantly in the unsuppressed hybrids, a revertant of one suppressed clone, or subclones of SUSM-1 used as controls. In the suppressed microcell hybrids, the distribution of a mortality marker, mortalin, was changed to the cytosolic type of mortal cells from the immortal type of perinuclear fibres. Also, senescence-associated beta-galactosidase was induced to a level similar to that of normally senesced diploid fibroblasts. These results suggest that human chromosome 7 induces senescence in SUSM-1 by suppressing its telomere maintenance mechanism, which does not depend on telomerase.

Animals↗

PubMed1997

DNA cleavage reaction and linoleic acid peroxidation induced by tea catechins in the presence of cupric ion.

Tea catechins with cupric ion promoted extensive DNA cleavage and fatty acid peroxidation in vitro under aerobic conditions. Neither cupric ions nor polyphenolic compounds including catechins alone induced DNA cleavage. While catalase significantly inhibited the DNA cleavage induced by catechins-Cu2+, superoxide dismutase (SOD) did not, indicating that H2O2 is probably involved in the DNA cleavage. These results suggest that the pro-oxidant property of catechins, which are generally considered to be anti-oxidants and anticarcinogens, is responsible for the O2 reducing ability of catechins catalyzed by cupric ion.

Aerobiosis↗

PubMed1997

The effect of silver administration on the biosynthesis and the molecular properties of rat ceruloplasmin.

To examine the cause of the altered ceruloplasmin (Cp) metabolism by silver administration, we analysed the properties of serum Cp by gel filtration chromatography, affinity chromatography and polyacrylamide gel electrophoresis. Metal contents in the Cp fraction from the silver-treated group were estimated as approximately 0.8 atom of silver and 4.2 atoms of copper per molecule, and as 5.9 atoms of copper for the control group. These findings confirm that holo-Cp from rat serum administered with silver nitrate exists as a silver-bound inactive form, suggesting that silver displaces one of Cp's copper atoms associating with oxidase activity. Matured holo-Cp also appeared in the Golgi in both groups, however, the amounts of enzymatically active holo-Cp showed a decrease after silver administration, while the apo-Cp level was hardly changed. These findings suggest that silver-bound holo-Cp is accomplished at Golgi.

Animals↗