PubMed Health⌕ Search

Biomedical subjects

Y Tamao

Publications and source records attributed to Y Tamao.

At least 37 records · Page 2Linked to original sources
PubMed1986

Effect of a selective thrombin inhibitor MCI-9038 on fibrinolysis in vitro and in vivo.

The effect of a selective thrombin inhibitor, (2R, 4R)-4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]- L-arginyl]-2-piperidinecarboxylic acid (MCI-9038), on the fibrinolysis induced by t-PA and u-PA was studied in vitro and in vivo. MCI-9038 remarkably reduced the lysis time of the plasma clot generated by the addition of calcium chloride to the plasma at the concentration ranging from 0.01 to 0.3 microM. Heparin also reduced the plasma clot lysis time with a lower effect than MCI-9038. The fibrin crosslinkage in the plasma clot was inhibited by MCI-9038 or heparin. MCI-9038 potently inhibited the factor XIIIa generation from factor XIII by thrombin. The effect on the in vivo thrombolysis was studied on the arterial thrombosis generated by the endothelial cell injury of the rabbit carotid artery by acetic acid. t-PA dissolved the thrombi with the infusion at 0.96 mg/kg over 2 h without a significant activation of a systemic fibrinolysis. u-PA dissolved the thrombi with the infusion at 180,000 and 360,000 IU/kg over 2 h. At a dose of 0.48 mg/kg t-PA or 90,000 IU/kg u-PA, the thrombi were not dissolved, but the combined use of MCI-9038 at 1.2 mg/kg over 2 h effectively dissolved the thrombi. Thus, combination of MCI-9038 with plasminogen activators accelerated thrombolysis of an experimental thrombosis in rabbits.

Animals↗
PubMed1986

[Effects of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (MCI-2016, bifemelane hydrochloride) on coagulation, fibrinolysis, hemolysis, hemorheological properties and platelet aggregation].

MCI-2016 showed little influence on coagulation (APTT) and fibrinolysis (plasma clot lysis activated by urokinase) at doses (concentrations) as high as 300 mg/kg, p.o. or 8.6 X 10(-4) M. Hemolytic action of MCI-2016 was only observed at the concentrations above 2 mM. The drug also showed no influence on blood glucose level (30-300 mg/kg, p.o.). Effects of MCI-2016 on hemorheological properties were studied either in vitro or ex vivo. Above the doses (concentrations) of 100 mg/kg, p.o. and 10 microM, MCI-2016 suppressed the mechanical hemolysis and accelerated the membrane filtration rate. These effects of MCI-2016 were superior to those of cinepazide, Ca-hopantenate, meclofenoxate and pentoxyfylline. MCI-2016 also inhibited platelet aggregation induced by collagen with the IC 50 of 35 to 60 microM (rabbit and human platelets). Secondary aggregations of ADP and epinephrine were also inhibited by MCI-2016. As for reference drugs, bencyclane showed inhibitory patterns similar to MCI-2016. Other drugs examined exhibited little effect. In summary, it may be suggested that MCI-2016 exhibits beneficial influences in the clinical fields of cerebrovascular diseases.

Animals↗
PubMed1984

Selective inhibition of thrombin by (2R,4R)-4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl++ +) sulfonyl]-l-arginyl)]-2-piperidinecarboxylic acid.

The potency of thrombin inhibition by 4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-sulfony l]- L-arginyl]-2-piperidinecarboxylic acid (MQPA) depended on the stereoconformation of the 2-piperidinecarboxylic acid moiety. Ki values for bovine alpha-thrombin were 0.019 microM with (2R,4R)-MQPA, 0.24 microM with (2R,4S)-MQPA, 1.9 microM with (2S,4R)-MQPA, and 280 microM with (2S,4S)-MQPA. (2R,4R)-MQPA of the four stereoisomers of MQPA was also the most potent inhibitor for other trypsin-like serine proteases with Ki values of 5.0 microM for trypsin, 210 microM for factor Xa, 800 microM for plasmin, and 1500 microM for plasma kallikrein. Examination of the potency of thrombin inhibition by arginine derivatives related to MQPA in structure suggested the presence of a specific binding site for the carboxamide portion (C-terminal side). The relative inhibitory potency of the four stereoisomers of MQPA for trypsin was nearly identical with that for thrombin, suggesting that the specific binding site for the carboxamide portion is present in both enzymes. Modification of thrombin by phosphopyridoxylation or the presence of heparin did not significantly alter the binding of MQPA.

Animals↗
PubMed1980

Thrombin inhibitors. 1. Ester derivatives of N alpha-(arylsulfonyl)-L-arginine.

A series of N alpha-(arylsulfonyl)-L-arginine esters was prepared and tested as inhibitors of the clotting activity of thrombin. N alpha-Dansyl-L-arginine methyl ester was the most inhibitory of the N alpha-(arylsulfonyl)-L-arginine methyl esters. The most potent inhibitors were the n-propyl and n-butyl esters of N alpha-dansyl-L-arginine with an I50 of 2 X 10(-6) M. Esters of unsaturated straight-chain alcohols with a chain length of four carbons were also as inhibitory as the n-butyl ester. The inhibitors were hydrolyzed by thrombin and trypsin more slowly than N alpha-tosyl-L-arginine methyl ester.

Animals↗
PubMed1980

Thrombin inhibitors. 2. Amide derivatives of N alpha-substituted L-arginine.

A series of N alpha-(arylsulfonyl)-L-arginine amide derivatives with substituted or unsubstituted naphthalene and heterocyclic compounds as the N alpha-substituent was prepared and tested as inhibitors of the clotting activity of thrombin. N-n-Butyl and N-n-butyl-N-methyl derivatives of N alpha-dansyl-L-arginine amide were the most inhibitory of N-alkyl and N,N-dialkyl derivatives of N alpha-dansyl-L-arginine amide. Their inhibitory effect was as potent as that of N alpha-dansyl-L-arginine-n-butyl ester with an I50 of 2 X 10(-6) M. N alpha-Substituted naphtalenesulfonyl-L-arginine amide derivatives of 4-methyl- and 4-ethylpiperidine also showed a potent inhibition with an I50 of 10(-7) to 10(-6) M. The most potent inhibitior in this study was 1-[N alpha-(4,6-dimethoxynaphthalene-2-sulfonyl)-arginyl]-4-methylpiperidine, with an I50 of 7.5 X 10(-8) M. Arginine amide derivatives of 4-methyl- or 4-ethylpiperidine with tetralin or an oxygen-containing heterocyclic compound as a N alpha-substituent showed an inhibition with an I50 less than 10(-5) M. N-Monosubstituted derivatives of N alpha-dansyl-L-arginine amide were not hydrolyzed at all by thrombin and were hydrolyzed very slowly by trypsin, and N,N-disubstituted derivatives were not hydrolyzed at all by both enzymes.

Amides↗
PubMed1980

Thrombin inhibitors. 3. Carboxyl-containing amide derivatives of N alpha-substituted L-arginine.

A series of N alpha-(arylsulfonyl)-L-arginine amide derivatives having carboxamide N-substituents with a carboxyl group was prepared and tested as inhibitors of the clotting activity of thrombin. The most inhibitory compounds were obtained when a carboxyl group was introduced into the carbon next to the amide nitrogen of N alpha-(arylsulfonyl)-L-arginine amide derivatives, e.g., N alpha-(arylsulfonyl)-L-arginyl-N-butyl-, N-(methoxyethyl)- or N-(tetrahydrofurfuryl)glycine and 4-alkyl-1-[N alpha-(arylsulfonyl)-L-arginyl]-2-piperidinecarboxylic acid, with an I50 of 1-3 X 10(-7) M.

Animals↗
PubMed1979

Kinetic studies on the selectivity of a synthetic thrombin-inhibitor using synthetic peptide substrates.

The synthetic thrombin-inhibitor termed No. 205 (N-alpha-dansyl-L-arginine-4-ethyl-piperidine amide) found in our laboratories was studied kinetically using synthetic peptide substrates. The following results were obtained. 1. No. 205 inhibited thrombin competively with bz-Phe-Val-Arg-pNA and the Ki value obtained was extremely small, 3.7 x 10(-8) M. 2. No. 205 also inhibited trypsin competitively with bz-Phe-Val-Arg-pNA but the Ki value obtained was far larger than that for thrombin, 1.0 x 10(-5) M. 3. No. 205 inhibited F. Xa, plasmin and urokinase only to a small extent when estimated using 2 x 10(-4) M D-Val-Leu-Lys-pNA, bz-Ile-Glu-Gly-Arg-pNA and Glu-Gly-Arg-pNA, respectively. 4. No 205 differed from APPA in its specific inhibitory spectrum for thrombin as compared to trypsin, plasmin and F. Xa. The above results indicate that No. 205 is an extremely potent and highly selective reversible thrombin-inhibitor.

Animals↗