Biomedical subjects

N Kaneda

Publications and source records attributed to N Kaneda.

At least 37 records · Page 2Linked to original sources

PubMed1997

Intravenous administration of irinotecan elevates the blood beta-glucuronidase activity in rats.

7-Ethyl-10-hydroxycamptothecin (SN-38) is the active metabolite of an anticancer drug, irinotecan (CPT-11). Severe late diarrhea is the dose-limiting toxic effect of CPT-11. This diarrhea has been examined regarding biliary excretion and deconjugation of SN-38 glucuronide by the enzyme beta-glucuronidase (beta-GL) in intestinal microflora. Prompted by the enzymological and structural similarity of CPT-11 to organophosphorus and carbamate insecticides, we studied the effect of CPT-11 on blood beta-GL activity in rats. The i.v. injection of CPT-11 in rats significantly elevated their plasma beta-GL activity (with phenolphthalein glucuronide as a substrate) at doses of 10 and 40 mg/kg, with peak activity observed 2-3 h after administration. SN-38 lactone and carboxylate had no effect on the plasma beta-GL level. The enhancement of the activity was also observed in serum using SN-38 glucuronide as a substrate. The serum beta-GL levels showed a close correlation between these substrates. The enhancement of plasma (serum) beta-GL activity is suggested to be a result of the release of beta-GL from liver microsomes. Serum and microsomal carboxylesterase were not significantly affected by CPT-11 administration.

Animals↗

PubMed1997

Identification of heparin-binding sites in midkine and their role in neurite-promotion.

Midkine (MK) is a heparin-binding growth factor, which promotes neurite outgrowth in embryonic neurons and enhances their survival. The three dimensional structure of MK clarified by NMR spectroscopy indicates that several basic amino acids are exposed on the surface of the C-terminal half domain, which retains heparin-binding and neurite-promoting activity. We performed site-directed mutagenesis of these amino acids, and found that mutation of arginine78 reduced the heparin-binding activity. Mutation of either lysine83 or lysine84 scarcely affected heparin-binding activity, while the double mutant involving both lysine residues showed reduction in the activity. Neurite-promoting activity of mutant MKs always correlated with their heparin-binding activity, illustrating the close relationship of the two activities. Thus, the present result verifies the occurrence of two distinct heparin-binding sites involved in neurite-promoting activity of MK molecule.

Animals↗

PubMed1997

Aceclofenac blocks prostaglandin E2 production following its intracellular conversion into cyclooxygenase inhibitors.

Aceclofenac, 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid, is a novel non-steroidal anti-inflammatory drug. We investigated the effects of aceclofenac on prostaglandin E2 production by several kinds of human cells. Aceclofenac inhibited interleukin-1beta-induced prostaglandin E2 production by human rheumatoid synovial cells, but had no inhibitory effect on cyclooxygenase-1 or cyclooxygenase-2 activities by itself. We also observed that part of the aceclofenac was converted into diclofenac, the cyclooxygenase-1 and cyclooxygenase-2 inhibitor, when aceclofenac was incubated with human rheumatoid synovial cells. Aceclofenac was also converted into diclofenac and 4'-hydroxy diclofenac by human polymorphonuclear leukocytes and monocytes. 4'-Hydroxy diclofenac suppressed prostaglandin E2 production specifically by blocking cyclooxygenase-2 activity. These findings suggested that aceclofenac can be metabolized to cyclooxygenase inhibitors (diclofenac and/or 4'-hydroxy diclofenac) by these inflammatory cells. Although detailed examinations in non-inflammatory cells remain to be studied, we concluded that aceclofenac is shown to be a new type of non-steroidal anti-inflammatory drug which is intracellulary converted into active metabolites that inhibit the prostaglandin E2 production.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1997

Metanestin, a glycoprotein with metastasis-associated expression in transitional cell carcinoma of the urinary bladder.

A 60-kDa glycoprotein named metanestin was identified by molecular cloning. The glycoprotein had a twice-repeated motif of Pro-Gly-Pro-Gly and carried metastasis-associated carbohydrate epitopes. The antibody to the protein portion of metanestin strongly reacted with lymph-node metastasis of transitional-cell carcinoma of the urinary bladder, but the reactivity to the primary tumor was generally weaker and the normal urothelium was scarcely reactive. Thus both metanestin and the carbohydrate on it showed metastasis-associated expression. In addition, we identified a 100-kDa glycoprotein with a 4-times-repeated motif of Pro-Ala-Pro-Ala. The antibody to the 100-kDa glycoprotein showed reactivity similar to that to metanestin.

Amino Acid Sequence↗

PubMed1997

Association of body mass index, physical activity, and reproductive histories with breast cancer: a case-control study in Gifu, Japan.

To further clarify risk factors for breast cancer in Japanese women, a self-administered questionnaire was completed by 157 cases with histologically confirmed breast cancer from 1989 to 1993 and by 369 age and residential area matched controls in Gifu, Japan. Conditional logistic regression model was used to assess the relations. Multivariate analyses showed that breast cancer risk decreased with body mass index for premenopausal women (RR = 0.45; 95 % CI = 0.22-0.92 for BMI > or = 23 vs. < 21 (kg/m2)), but the risk increased with body mass index for postmenopausal women (RR = 1.98; 95 % CI = 0.86-4.55 for BMI > or = 24 vs. < 21.5 (kg/m2)). The risk increased with a small number of births in pre- and post-menopausal women (1.83; 1.11-2.99 and 6.06; 2.40-15.3 for 1-2 births and nulliparity, respectively, vs. > or = 3 births). Ex- or current smoking increased the risk of breast cancer (2.31; 1.19-4.49). Reduced risk of premenopausal breast cancer was associated with high energy expenditure in physical activity during teenage, although the trend was not statistically significant.

Adult↗

PubMed1997

Fat and fiber intakes in relation to serum estrogen concentration in premenopausal Japanese women.

It has been implied that fat and fiber intakes influence breast cancer risk. The effects of these dietary factors may be mediated by hormonal changes. We evaluated the relationships between fat or fiber intake and serum concentration of estradiol (E2) or sex hormone-binding globulin in premenopausal women. In 1994 blood samples were collected from each of 50 premenopausal healthy Japanese women on Days 11 and 22 of the menstrual cycle. Nutrient intakes were assessed by food frequency questionnaire in which the subjects were asked about their diets during one year before the study. Each nutrient intake was categorized into tertile after adjustment for total energy. Linear regression models, including age and cycle length as covariates, were utilized to evaluate the association between the nutrient intakes and the hormone concentrations. A statistically significant trend was observed between increasing fat intake and increasing E2 on Day 11 of the cycle (p = 0.05). The positive trend for increasing sex hormone-binding globulin on Day 22 with fat intake was of borderline significance (p = 0.06). There was a statistically significant inverse trend for E2 on Day 11 of the cycle with fiber intake (p = 0.05). It was suggested that fat as well as fiber intake should affect the hormone status.

Adult↗

PubMed1997

A novel truncated variant form of Ebk/MDK1 receptor tyrosine kinase is expressed in embryonic mouse brain.

We have isolated cDNA clones from a mouse embryonic head cDNA library that encode one member of the Eph/Eck family of receptor tyrosine kinases (RTKs), Ebk/MDK1. Among the 10 clones, two showed full-length type comprising extracellular, transmembrane and intracellular kinase domains. Two of them were modified just after the transmembrane domain and stop codon appeared before completing the kinase domain. This truncated form also had a deletion of five amino acids at the extracellular domain, indicating that it is a novel variant of Ebk/MDK1. RNase protection assay showed that this truncated deleted type, named Ebk-td1, is present in the head of embryos, although the amount is less compared to that of the full-length type having a deletion of four amino acids. Considering the source and expression of Ebk/MDK1 mRNAs, they may have an important role, accompanied with a possible regulatory role of the truncated variant, during neural development and/or in embryogenesis.

Amino Acid Sequence↗

PubMed1997

Simultaneous determination of the lactone and carboxylate forms of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan (CPT-11), in rat plasma by high performance liquid chromatography.

We established a high performance liquid chromatography (HPLC) method for the simultaneous determination of the lactone and carboxylate forms of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of the antitumor drug irinotecan (CPT-11), in rat plasma. Plasma samples were pretreated with chilled MeOH and zinc sulfate to precipitate protein, and were then directly injected into the HPLC system. Chromatography was carried out with a Puresil C18 column (particle size 5 microns), and the mobile phase consisted of 0.1 M ammonium acetate buffer (pH 5.5) and acetonitrile (70/30, v/v) containing 20 mM of tetra-n-pentylammonium bromide. The column effluent was monitored with a spectrofluorometer (excitation wavelength 380 nm, emission wavelength 540 nm). The method was valid for SN-38 lactone (5-2500 ng/ml) and carboxylate (5-1000 ng/ml).

Animals↗

PubMed1997

Plasma pharmacokinetics of 7-ethyl-10-hydroxycamptothecin (SN-38) after intravenous administration of SN-38 and irinotecan (CPT-11) to rats.

We studied the plasma pharmacokinetics of the lactone form and the carboxylate form of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan (CPT-11), after intravenous bolus administrations of each form of SN-38 and of CPT-11 to rats. After the SN-38 lactone injection, SN-38 lactone was predominant at first, and then the lactone to the carboxylate concentration ratio (LC ratio) was maintained from 30 to 90 min after the injection. The carboxylate was predominant throughout the period after the carboxylate dosing. Model-dependent analyses showed that the SN-38 lactone had greater plasma clearance and a greater distribution volume than the carboxylate. The CPT-11 administration resulted in a predominant plasma SN-38 lactone concentration. The contribution of the SN-38 lactone AUC to the total SN-38 AUC (57%) was independent of the dose of CPT-11. These results suggest that it is possible to estimate the SN-38 lactone concentration and AUC from the total SN-38 concentration without separate determination of the lactone and carboxylate. Our results showed that both SN-38 lactone and CPT-11 administration gave the predominant SN-38 lactone in plasma; however, only CPT-11 could sustain the lactone concentration at a high level, which is necessary for antitumor activity.

1-Octanol↗

PubMed1997

Factors associated with serum levels of estradiol and sex hormone-binding globulin among premenopausal Japanese women.

We measured serum levels of estradiol (E(2)) and sex hormone-binding globulin (SHBG) among 50 healthy premenopausal Japanese women in 1994 in Gifu, Japan, to investigate the relationships between potential risk factors for breast cancer and hormone levels. Using a self-administered questionnaire, we collected data on body size, physical activity, and previous disease history, as well as menstrual and reproductive histories of the woman and her mother. Blood samples were drawn from each subject on the 11th and 22nd days of her menstrual cycle. Higher serum E(2) levels were observed for women with shorter menstrual cycles. Age as well as cycle length were included in the regression models to determine the associations between hormone levels and study variables. Body mass index (BMI) was inversely related to SHBG level measured at the 11th day of the cycle, after adjusting for age and cycle length (r = -0.33; p = 0. 03). Women born in spring/summer had higher levels of E(2) on the 22nd day (p = 0.07) and higher levels of SHBG on both the 11th and 22nd days of the cycle (p = 0.01 and p = 0.06, respectively) than those born in other seasons. Physical activity at 13-15 years of age was inversely related to E(2) level on the 11th day of the cycle after controlling for age, cycle length, BMI, and birth month (r = -0.35; p = 0.04).

Adult↗

PubMed1996

Limited proteolysis by chymotrypsin of midkine and inhibition by heparin binding.

When digested with a low concentration of chymotrypsin, midkine (MK) underwent limited proteolysis and produced two fragments with Mr of 11,000 and 6,000 Da. The cleavage site was identified as on the carboxyl side of Phe55. This limited proteolysis was specifically inhibited by heparin, but not by other glycosaminoglycans. Using various heparin-derived oligosaccharides with different chain lengths or chemically desulfated heparin derivatives, it was shown that a minimum of 6 monosaccharide units was necessary for the inhibition, and that sulfonyl groups of the heparin disaccharide unit were required for inhibition. The present study showed that MK consists of two domains, N- and C-domains, and that Phe55 localized to the hinge region is exposed on the surface of the molecule. It was also suggested that the N-domain may function as a stabilizing domain against proteolytic degradation of the C-domain in the intact molecule.

Amino Acid Sequence↗

PubMed1996

Structural characteristics of heparin-line domain required for interaction of midkine with embryonic neurons.

Midkine is a heparin binding growth/differentiation factor with neurite promoting activity. We examined inhibitory activities of various heparin derivatives toward interaction of midkine with neurons and elucidated the structural requirements of the heparin-like domain necessary for the interaction. All of the three sulfate groups in the heparin disaccharide unit (6-O-sulfate, 2-O-sulfate and N-sulfate) were necessary for full inhibitory activity. Among these, the N-sulfate group was critically important. The minimum size with inhibitory activity was approximately 7,000 Da. Thus, the highly sulfated region in cell surface heparan sulfate proteoglycan is required for neurons to interact with midkine.

Animals↗

PubMed1996

Midkine, a heparin-binding growth/differentiation factor, exhibits nerve cell adhesion and guidance activity for neurite outgrowth in vitro.

By means of a baculovirus expression system, a large amount of mouse midkine (MK) was produced. The protein was purified to homogeneity by heparin-Sepharose column chromatography. The purified protein was of a mature type; the signal peptide was cleaved at the expected site. To examine the neurite-guiding activity of MK, rat embryonic brain cells (embryonic days 17-18) were cultured on plates coated with purified MK in a grid pattern. The cells attached to and extended their neurites along the substrate pattern. This interaction was strongly inhibited by heparin, but not by other glycosaminoglycans. Treatment of the cells with heparitinase was effective for inhibiting their adhesion to the substrate. These data suggest that the heparin-like domain on cell surface heparan sulfate proteoglycan is the primary site for MK binding upon interaction with nerve cells.

Amino Acid Sequence↗

PubMed1996

[Post dural puncture headache (PDPH) which occurred after the removal of an epidural catheter].

A 57-year-old man received gastrectomy under general anesthesia combined with epidural anesthesia. He showed no signs of dural puncture and catheter migration into the subarachnoid space. Cardiovascular status was stable with epidural injection of lidocaine, morphine during the operation. Although epidural morphine and buprenorphine infusions were continued for 1 to 6 postoperative days, respiratory depression and other side effects were not observed. However, severe headache in the upright position occurred after stopping these infusions and the removal of the catheter on the 7th postoperative day. The headache was thought to be caused by unintentional dural puncture. PDPH persisted over a period of 30 days and was treated with an epidural blood patch and stellate ganglion blocks since the other conservative therapy had been ineffective. We consider that administration of continuous epidural opioids for postoperative analgesia helped to prevent PDPH until the 7th postoperative day. We also conclude that prolonged PDPH after using a thick needle like a Touhy needle should be treated by an epidural blood patch.

Anesthesia, Epidural↗

PubMed1995

A new enzymatic method for the determination of inulin.

A new enzymatic method for the determination of inulin in plasma and urine, using inulase (EC 3.2.1.7), fructokinase (EC 2.7.1.4), phosphoglucoisomerase (EC 5.3.1.9) and glucose-6-phosphate dehydrogenase (EC 1.1.1.49) is described. The assay is based on the hydrolysis of inulin or Inutest (INutest which is the injectable form of inulin), by inulase and the determination of fructose released. The assay was linear up to 2 g/L of Inutest. The within-batch and between batch coefficients of variation were 2.3% and 2.2%, respectively. Recovery of added Inutest from plasma and urine was 98-102%. There was no interference from glucose (27.7 mmol/L), fructose (1.7 mmol/L) or mannose (1.7 mmol/L). When inulin clearance (using this method) and thiosulphate clearance were compared in 37 patients the inulin clearance was 9.3 mL/min (12%) lower than the thiosulphate clearance. We conclude that this enzymatic method is a simple and specific method.

Anthracenes↗

PubMed1994

Effects of CPT-11 (a unique DNA topoisomerase I inhibitor) on a highly malignant xeno-transplanted neuroblastoma.

Although many advances have been made in the management of neuroblastoma, the prognosis of patients with advanced neuroblastoma remains poor, and constant efforts are being made to search for newer effective drugs. CPT-11 is a newly developed derivative of camptothecin and shows a unique anti-tumor activity by inhibiting DNA topoisomerase I. In this study the effects of CPT-11 on a human neuroblastoma xenograft, TNB9, were investigated according to the standard Battelle Columbus Laboratories protocol. TNB9 is one of the most malignant strains of neuroblastoma, showing a homogeneously staining resion (HSR) on chromosome 20 and 80-fold amplification of the N-myc gene. This study disclosed that CPT-11 was highly effective against TNB9. Maximum inhibition rate (IR) was 72.5% at a standard dose and 52.8% even at half the dose. No nude mouse used in this study lost weight after an administration of CPT-11. Plasma pharmacokinetics of CPT-11 administered in this experimental model were compared to that in clinical patients. Our data suggested that CPT-11 might be a promising new drug in the treatment of high-risk neuroblastoma patients and encouraged us to employ CPT-11 in the protocol of the Study Group of Japan.

Animals↗

PubMed1994

Fibrin-specific fibrinolysis induced by recombinant staphylokinase.

We compared the thrombolytic properties of recombinant staphylokinase (SAK) with those of streptokinase (SK), a tissue-type plasminogen activator (t-PA) and a urokinase-type plasminogen activator (u-PA) in the jugular vein thrombosis model in the rabbit in vivo and a circulating human plasma system in vitro. 50% thrombolysis was observed at 360 min after intravenous infusion into rabbits of 150 micrograms/kg of SAK or 500 micrograms/kg of t-PA, respectively. And the fibrinogen level in the blood was not affected by either agent. 50% clot lysis in vitro was observed at 120 min with 1.8 micrograms/ml of SAK, 22.1 micrograms/ml of SK, 2.1 micrograms/ml of t-PA, or 4.7 micrograms/ml of u-PA, respectively. All the plasminogen activators with the exception of SAK decreased the residual fibrinogen level in the circulating plasma at their moderate concentration for clot lysis. SAK had less influence on the plasminogen and alpha 2-plasmin inhibitor (alpha 2-antiplasmin) levels than the other plasminogen activators. These findings suggest that SAK is a potent fibrin-specific thrombolytic agent.

Animals↗

PubMed1994

Involvement of protease inhibitors in staphylokinase-induced fibrin-specific fibrinolysis.

We compared the fibrinolytic properties of recombinant staphylokinase (SAK), a fibrin-specific plasminogen activator, with those of streptokinase and tissue-type plasminogen activator (t-PA) by means of the amidolytic method. We also investigated the involvement of alpha 2-macroglobulin, C1-inactivator and alpha 1-antitrypsin in SAK-induced fibrin-specific fibrinolysis. Both SAK and t-PA activated plasminogen efficiently in the presence of fibrin in human plasma. Although t-PA activated plasminogen dependently on fibrin in the reconstituted plasma system, SAK activated plasminogen independently of fibrin without alpha 2-plasmin inhibitor (alpha 2-antiplasmin, alpha 2-PI). These findings suggest that fibrin and alpha 2-PI play important roles in plasminogen activation by SAK but not by t-PA. Furthermore, protease inhibitors such as alpha 2-PI, alpha 2-macroglobulin, C1-inactivator and alpha 1-antitrypsin inhibited plasminogen activation by SAK and the inhibitory actions of these protease inhibitors disappeared in the presence of fibrin. This shows that alpha 2-macroglobulin, C1-inactivator and alpha 1-antitrypsin, other than alpha 2-PI, contribute to the fibrin-specificity of SAK.

Amino Acid Sequence↗