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Biomedical subjects

S Kawabata

Publications and source records attributed to S Kawabata.

At least 199 records · Page 11Linked to original sources
PubMed1990

Synthesis and antibacterial activity of the metabolites of 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H,5H- benzo[i,j]quinolizine-2-carboxylic acid (OPC-7251).

The metabolites of 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H,5H- benzo[i,j]quinolizine-2-carboxylic acid (OPC-7251) (1), which has a potent antibacterial activity against gram-positive bacteria, characteristically Propionibacterium acnes, were synthesized to confirm their structures and to examine their antibacterial activity. The structures of three major metabolites (2, 3a and 4) were identified by means of comparison with the synthetic compounds. The antibacterial activity of the metabolites (2, 3a and 4) was found to be lower than that of 1.

Anti-Bacterial Agents↗
PubMed1990

[Follow-up study of short course chemotherapy of pulmonary tuberculosis complicated with diabetes mellitus].

A retrospective analysis was made for 644 patients with pulmonary tuberculosis newly diagnosed during the time of 1977 to 1985 to evaluate the influence of diabetes mellitus (DM) on the drug response rate and the long-term relapse rate in the treatment of tuberculosis. These patients were divided into four groups: (1) 123 patients with DM on 9- to 12-month short course regimens; (2) 79 with DM on 13- to 36-month long-term regimens; (3) 379 nondiabetic patients on short-term regimens; and (4) 63 nondiabetics on long-term regimens. Bacteriological relapse after chemotherapy was defined as positive cultures growing at least 20 or more colonies. 1) Bacteriological negative conversion rates were similar in both diabetic and nondiabetic patients who had received combination regimens including INH and RFP. The degree of control of DM did not affect the conversion rate. 2) Of 297 patients who had received short-course chemotherapy and the information for analysis were available as of August 1989, 8 (10.3%) had relapses in 78 diabetic, and patients 23 (10.5%) in 219 non-diabetic patients; the difference was not statistically significant. There were also no discernible differences in the relapse rates between patients on the short-course regimens and those on the long-term regimens. 3) Most of the relapses occurred around 6 months and 30 months after completing the short-course chemotherapy. Similar pattern of relapses was observed also in the long-term therapy group. 4) Pretreatment radiographic findings and quantity of the acid-fast bacilli in the sputum, and the presence of cavitary lesions at the completion of therapy bore no significant relation to the development of relapse. 5) In the diabetic patients the degree of control of DM contributed little to the development of recurrence. 6) Although most of the patients without DM relapsed with sensitive strains and achieved a good response to retreatment, diabetic patients frequently relapsed with resistant strains and had a grave prognosis. 7) Of 41 patients who died after having been on the short-course regimens, two were attributed to tuberculosis. Only one was attributed to tuberculosis of 25 patients who died after receiving the long-term regimens. 8) The data obtained here confirmed that the 12-month regimen for diabetic patients could achieve favorable results in the response rate and the long-term relapse rate, as that for nondiabetic patients. However the cases of tuberculosis complicated with DM frequently showed a poor prognosis once the relapse took place. These results suggest that pyrazinamide-containing 4-drug combination regimens in an initial intensive phase is the preferred treatment for the patients with DM.

Adult↗
PubMed1989

Blood clotting factor IX BM Nagoya. Substitution of arginine 180 by tryptophan and its activation by alpha-chymotrypsin and rat mast cell chymase.

Factor IX BM Nagoya (IX Nagoya) is a natural mutant of factor IX responsible for severe hemophilia B. A patient with this mutant is characterized by a markedly prolonged ox brain prothrombin time. IX Nagoya was purified from the patient's plasma by immunoaffinity chromatography with an anti-factor IX monoclonal antibody column. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that treatment of IX Nagoya with factor XIa/Ca2+ resulted in cleavage only at the Arg145-Ala146 bond. Reversed-phase high performance liquid chromatography of a trypsin digest of IX Nagoya showed an aberrant peptide, which was further digested with proteinase Asp-N. Primary structure analysis of one of the Asp-N peptides revealed that Arg180 is replaced by Trp. An essentially complete (99%) amino acid sequence of IX Nagoya was obtained by sequencing fragments derived from a lysyl endopeptidase digest in which no other substitutions in the catalytic triad or substrate binding site were found. We also found that IX Nagoya is activated by alpha-chymotrypsin or rat mast cell chymase by monitoring the rate of factor X activation using a fluorogenic peptide substrate in the presence of factor VIII, phospholipids, and Ca2+. These results indicate that the substitution of Arg180 by Trp impairs the cleavage by factor XIa required for activation of this zymogen and that the substitution causes hemophilia BM.

Amino Acid Sequence↗
PubMed1989

Identification of a disaccharide (Xyl-Glc) and a trisaccharide (Xyl2-Glc) O-glycosidically linked to a serine residue in the first epidermal growth factor-like domain of human factors VII and IX and protein Z and bovine protein Z.

We have recently described a unique trisaccharide linked to a serine residue in the first epidermal growth factor-like domains of bovine blood coagulation factors VII (Ser-52) and IX (Ser-53) (Hase, S., Kawabata, S., Nishimura, H., Takeya, H., Sueyoshi, T., Miyata, T., Iwanaga, S., Takao, T., Shimonishi, Y., and Ikenaka, T. (1988) J. Biochem. (Tokyo) 104, 867-868). The sugar chain identified in these clotting factors consists of 1 mol of hexose (glucose (Glc] and 2 mol of pentose (xylose (Xyl]. We report here that human factors VII and IX and protein Z and bovine protein Z also contain such carbohydrate moieties linked to a serine residue at the same position found in bovine factors VII and IX. A glycopeptide derived from each of these proteins was subjected to amino acid sequence and component sugar analyses and fast atom bombardment mass spectrometric analysis. The results indicate that the glycopeptide derived from human factor IX contains 1 mol each of Glc and Xyl. The reducing end of this disaccharide was identified as Glc by analyzing the disaccharide generated by hydrazinolysis. In contrast, human factor VII and protein Z yielded two different glycopeptides which contained Glc and Xyl at molar ratios of 1:1 and 1:2, respectively, suggesting microheterogeneity of these O-linked sugar chains. Bovine protein Z glycopeptide contained 1 mol of Glc and 2 mol of Xyl. These sugar compositions were confirmed by analyses of the intact proteins. In relation to the trisaccharide sugar chain previously discovered in bovine factors VII and IX, these findings indicate the existence of a Xyl2-Glc-Ser and a Xyl-Glc-Ser structure in the first epidermal growth factor-like domains of human factors VII and IX and protein Z in addition to that of bovine protein Z. Whether these carbohydrate moieties contribute to the biological activities of these proteins is unknown.

Amino Acid Sequence↗
PubMed1989

Effects of indeloxazine hydrochloride on passive avoidance behavior of senescence-accelerated mice.

The effects of indeloxazine hydrochloride on disturbances of passive avoidance behavior in senescence-accelerated mice (SAM) were observed. The step-through latency of SAM-P/8/Ta (SAM-P/8, senescence-prone substrain) was significantly shorter than that of SAM-R/1/Ta (SAM-R/1, senescence-resistant substrain). The administration of indeloxazine (10-30 mg/kg p.o.) or dihydroergotoxine (1 mg/kg i.p.) for 3 weeks significantly prolonged the step-through latency of SAM-P/8/Ta whereas piracetam (30-300 mg/kg p.o.) did not. These results suggest that indeloxazine has a facilitatory effect on cerebral functions and that it has a broader pharmacological profile in anti-amnesic activities than piracetam.

Aging↗
PubMed1989

Characterization of mitomycin C-induced gastrointestinal damage. I. In situ recirculation experiment.

The effects of mitomycin C (MMC), an anti-tumor agent, on the intestinal absorption of various drugs in rats were investigated. Based on microscopic observations, preadministration of a single intravenous dose of MMC (3 mg/kg) caused serious degeneration of epithelial cells, villous atrophy, and mitotic arrest in crypts at 48 hr after pretreatment. At this time point, absorption of sulfanilamide, salicylic acid, cephalexin, and L-tryptophan was shown to be significantly decreased by means of an in situ recirculation technique. The histological changes and the decrease in absorption of sulfanilamide, a model for passively absorbed drugs, were shown to depend on the timing of MMC pretreatment. Maximal effects were observed 48 hr after dosing. The MMC-induced reduction in the absorption of drugs was not a result of differences between treated and control animals with respect to pH of the drug solution, binding of drugs with intraluminal macromolecules, or intestinal mucosal blood flow. The absorption of sulfanilamide from the small intestine in the in situ system correlated well with the wet weight of the small intestine regardless of pretreatment dose or route. This suggests that the change in absorptive surface area of the intestinal mucosa may play a major role in the MMC-induced decrease in absorption capacity of the intestine.

Animals↗
PubMed1989

Pharmacological effects of indeloxazine, a new cerebral activator, on brain functions distinct from other cerebral metabolic enhancers.

The effects of indeloxazine hydrochloride [(+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride, YM-08054], a new cerebral metabolic enhancer, on learned behavior and central monoaminergic function were compared to those of other cerebral metabolic enhancers in animals. Indeloxazine enhanced passive learned behaviour in rats and ameliorated cerebral ischemia-induced learned disturbances in gerbils. Reserpine-induced hypothermia in mice, ponto-genicullo-occipital (PGO) waves in reserpinized cats and caudate spindle activity in cats were reduced by the administration of indeloxazine, suggesting that the drug possesses facilitatory effects on central monoaminergic systems. In contrast, piracetam, calcium-hopantenate, idebenone and bifemelane had no significant effect on learned behavior or central monoaminergic function, with the exception of bifemelane which antagonized reserpine-induced hypothermia. These results are in contrast to the findings that all tested cerebral metabolic enhancers, including indeloxazine, prolonged the survival time of mice subjected to anoxia. The greater effect of indeloxazine to other cerebral metabolic enhancers, in facilitating learned behavior, may be attributable to its broader effects on central monoaminergic systems.

Animals↗
PubMed1989

Cerebral vasodilators potentiate the anti-anoxic activity of indeloxazine hydrochloride, a new cerebral activator.

Effects of some cerebrovasodilators on the anti-anoxic activity of indeloxazine hydrochloride [(+/-)-2[(inden-7-yloxy)methyl]morpholine hydrochloride, YM-08054] with cerebral metabolic enhancing activity, were observed in mice. Oral administration of both indeloxazine (10 mg/kg) and each of the cerebral vasodilators, such as nicardipine (10 mg/kg), cinepazide (100 mg/kg), ifenprodil (1 mg/kg), pentoxyfylline (1 mg/kg) and vinpocetine (10 mg/kg) significantly prolonged the survival time of mice subjected to anoxia, without affecting pentobarbital-induced sleeping time. The effect of indeloxazine was potentiated by a sub-effective dose of the cerebral vasodilators. The effect of a combined treatment may be due to the cerebral metabolic enhancing and vasodilating activities of both drugs. These results demonstrate the beneficial pharmacological properties of the combined treatment with indeloxazine and cerebrovasodilator and encourage combination therapy for the treatment of organic brain syndromes.

Animals↗
PubMed1989

Coagulation factor XII (Hageman factor) Washington D.C.: inactive factor XIIa results from Cys-571----Ser substitution.

Structural studies on a congenital abnormal coagulation factor XII (Hageman factor), factor XII Washington D.C., have been performed to identify the defect responsible for its lack of procoagulant activity. Amino acid sequence analysis of a tryptic peptide isolated from the abnormal factor XII indicated that Cys-571 (equivalent to Cys-220 in the chymotrypsin numbering system) had been replaced by serine. No other substitutions in the active-site triad--namely, His-393, Asp-442, and Ser-544--were found. We propose that the Cys-571----Ser replacement found in this factor XII variant destroys the formation of the disulfide linkage between Cys-540 and Cys-571, giving rise to an altered conformation of the active-site serine residue or the secondary substrate-binding site and, thus, leads to the loss of enzyme activity.

Amino Acid Sequence↗
PubMed1989

Factor IX Kawachinagano: impaired function of the Gla-domain caused by attached propeptide region due to substitution of arginine by glutamine at position -4.

Factor IX Kawachinagano (KWC) is a mutant factor IX protein initially recognized in a patient with severe haemophilia B, who had 46% of normal factor IX antigen and no detectable clotting activity. Previous studies indicated that factor IX KWC was not activated by factor XIa in the presence of Ca ions. In the present study, we purified and analysed factor IX KWC at a structural level in an attempt to clarify the nature of the impaired reaction with factor XIa. Kinetic studies showed that activation of factor IX KWC by factor X activator from Russell's viper venom (RVV-X) was normal, whereas activation by factor XIa was defective. Amino acid sequence analysis of tryptic peptides and direct analysis of the NH2-terminal sequence of factor IX KWC demonstrated that this mutant factor IX retained the propeptide region of 18 amino acids due to a substitution of arginine-(-4) by glutamine. These data suggested that the Gla-domain of factor IX KWC was dysfunctional, although the total gamma-Gla content, measured by alkaline-hydrolysis, was normal. We assumed that this attached propeptide region of the molecule directly interferes with the adjacent NH2-terminus and prevents the metal-induced conformational changes which are essential for biological activity of normal factor IX.

1-Carboxyglutamic Acid↗
PubMed1989

A cryptic fimbrial gene in Serratia marcescens.

The gene coding for the mannose-sensitive hemagglutinating fimbriae in Serratia marcescens US5 was cloned into Escherichia coli K4 with a cosmid vector system. One of the transformants, US5-1, expressed two morphologically distinct fimbriae, one that was 5-nm wide and one that was 3-nm wide. The latter fimbria was morphologically and serologically indistinguishable from that of strain US5. Genetic analysis of transformant US5-1 showed that the gene responsible for the 5-nm-wide fimbriae was located more than 10 kilobases away from the gene responsible for the 3-nm-wide fimbriae. The molecular sizes of the subunits of these two fimbriae, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, were 19 kilodaltons for the 3-nm-wide fimbriae and 20 kilodaltons for the 5-nm-wide fimbriae. Serologically, the 5-nm-wide fimbriae did not cross-react with monoclonal or polyclonal antibodies raised against the mannose-sensitive hemagglutinating fimbriae of strain US5. Strain EL101, which expressed only the 5-nm-wide fimbriae, did not agglutinate chicken or human erythrocytes. These experimental results suggest that the gene for the 5-nm-wide fimbriae is cryptic in strain US5 and is expressed in E. coli K4 only after it is moved by transformation.

Amino Acid Sequence↗
PubMed1989

[Caries-inducing activity of isomaltooligosugar (IMOS) in in vitro and rat experiments].

The caries-inducing activity of Isomaltooligosugar (IMOS: a isomaltose rich sugar mixture) was examined in in vitro and in vivo experiments. Strains of Streptococcus mutans MT8148R and Streptococcus sobrinus 6715 fermented IMOS and produced acids. IMOS inhibited the glucan synthesis from sucrose by glucosyltransferases from both of S. mutans and S. sobrinus. Furthermore, IMOS inhibited sucrose-dependent adherence of those mutans streptococci. IMOS was found to induce significant but minimal caries SPF Sprague-Dawley rats infected with either MT8148R and 6715. However, IMOS did not inhibit the caries which was induced by sucrose.

Animals↗
PubMed1989

[Severe respiratory failure with pulmonary tuberculosis during initial phase of chemotherapy].

In seven patients with tuberculosis required ventilatory assistance, in our IRCU at the Habikino Hospital, we found worsening of the findings on chest X-ray film and clinical status during initial phase of chemotherapy, although their sputum became negative for acid-fast bacilli. On admission, six of them had large infiltration with cavities and discharged a large number of bacilli with elevation of ESR and hypoalbuminemia. We could get four patents off ventilator after start of PEEP therapy and high dose corticosteroid therapy. But three of them died at last, because they developed severe respiratory failure again. Pulmonary histology was available in five patients. We found interstitial and intra-alveolar pulmonary edema, intra-alveolar organization, hyperplasia of alveolar wall, and hyaline membrane formation. These findings were compatible with diffuse alveolar damage.

Adult↗
PubMed1988

Bovine factor VII. Its purification and complete amino acid sequence.

A modified method for purification of blood clotting factor VII from bovine plasma was developed, and its complete amino acid sequence was established. The isolated factor VII was activated with factor XIIa, and the resulting two-chain factor VII (factor VIIa) was reduced and S-pyridylethylated or S-aminoethylated. The amino acid sequences of the S-alkylated heavy and light chains were determined by sequencing the fragments obtained from enzymatic and chemical cleavages. Fast atom bombardment mass spectrometry was also used to establish the COOH-terminal sequence of the heavy chain. The light chain consists of 152 residues with one carbohydrate chain at Asn145, and 11 gamma-carboxyglutamic acid residues are found within the NH2-terminal 35 residues. The light chain contains 0.2-0.3 mol of beta-hydroxyaspartic acid/mol of protein, indicating that an aspartic acid residue in bovine factor VII is incompletely hydroxylated. Moreover, a pentapeptide, Ala-Ser*-Ser-Pro-Cys (positions 51-55), isolated from an enzymatic digest of the light chain, contained an unknown serine derivative, but its structure is still unclear. On the other hand, the heavy chain is composed of 255 residues and one asparagine-linked carbohydrate chain at Asn203. Bovine factor VII, with a total of 407 residues, has 71% sequence identity with the human molecule (406 residues) predicted from the cDNA sequence (Hagen, F. S., Gray, C. L., O'Hara, P., Grant, F. J., Saari, G. C., Woodbury, R. G., Hart, C. E., Insley, M., Kisiel, W., Kurachi, K., and Davie, E. W. (1986) Proc. Natl. Acad. Sci. U. S. A. 83, 2412-2416).

Amino Acid Sequence↗
PubMed1988

Highly sensitive peptide-4-methylcoumaryl-7-amide substrates for blood-clotting proteases and trypsin.

Seventy-four peptide amides of 7-amino-4-methylcoumarin (Mec) of the type Boc-Xaa-Yaa-Arg-NH-Mec were newly synthesized and tested to find specific substrates for blood-clotting proteases and trypsin. The Xaa and Yaa residues of these substrates have been replaced by 12 and 15 different amino acids, respectively. Among these peptides, the followings were found to be most sensitive substrates for individual enzymes: Boc-Asp(OBzl)-Pro-Arg-NH-Mec (kcat = 160 s-1, Km = 11 microM, kcat/Km = 15,000,000 M-1 s-1) for human alpha-thrombin, Z-less than Glu-Gly-Arg-NH-Mec (kcat = 19 s-1, Km = 59 microM, kcat/Km = 320,000 M-1 s-1) for bovine factor Xa, Boc-Gln-Gly-Arg-NH-Mec (kcat = 5.8 s-1, Km = 140 microM, kcat/Km = 42,000) for bovine factor XIIa, Boc-Asp(OBzl)-Ala-Arg-NH-Mec (kcat = 9.2 s-1, Km = 120 microM, kcat/Km = 77,000 M-1 s-1) for bovine activated protein C, and Boc-Gly-Phe-Arg-NH-Mec (kcat = 29 s-1, Km = 230 microM, kcat/Km = 130,000 M-1 s-1) for bovine plasma kallikrein. Moreover, Boc-Glu(OBzl)-Ala-Arg-NH-Mec (kcat = 46 s-1, Km = 370 microM, kcat/Km = 120,000 M-1 s-1) was newly found as a good substrate for human factor XIa. Bovine trypsin effectively hydrolyzed peptide-NH-Mec substrates containing Ala and Pro at the P2 site. The most reactive substrate was Boc-Gln-Ala-Arg-NH-Mec (kcat = 120 s-1, Km = 6.0 microM, kcat/Km = 20,000,000 M-1 s-1).

Amino Acids↗
PubMed1988

Radioimmunoscintigraphy of xenografted human thyroid carcinoma.

We developed monoclonal antibodies against human thyroid cancer-associated antigen by fusing mouse myeloma cells with mouse spleen cells immunized by insoluble fraction of homogenized thyroid papillary carcinoma cells. One monoclonal antibody (KTC-3, IgM) was selected to evaluate basic usefulness for radioimmunoscintigraphy in xenografted human thyroid carcinoma. KTC-3 was labeled with 131I by Iodogen method of 20 to 1 Iodogen to IgM molar ratio. It was also labeled with 111In by cyclic DTPA anhydride method of 20 to 1 DTPA to IgM molar ratio. The labeling efficiency and specific activity for 131I labeling were 16.5% and 0.66 mCi/mg IgM respectively, and those for 111In labeling were 12.7% and 1.6 mCi/mg IgM. Imaging and biodistribution of labeled KTC-3 were evaluated in nude mice bearing thyroid anaplastic carcinoma (THC-5-JCK). The tumors were well visualized 3 and 5 days after injection of 131I KTC-3. Tumor uptake of 131I KTC-3 on day 7 was 0.52 +/- 0.27% ID/g and tumor to blood ratio was 1.98 +/- 0.76 (n = 6). Those of 111In KTC-3 were 0.88 +/- 0.09% ID/g and 5.51 +/- 3.36 (n = 6). In conclusion, KTC-3 is promising for radioimmunoscintigraphy of thyroid cancer.

Animals↗