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K Akamatsu

Publications and source records attributed to K Akamatsu.

At least 19 recordsLinked to original sources
PubMed1995

Endogenous ET-1 contributes to liver injury induced by galactosamine and endotoxin in isolated perfused rat liver.

Injury to hepatocytes most likely occurs via disturbances in the microcirculation. The role of vasoconstriction due to the effect of endogenous endothelin-1 (ET-1) in the development of galactosamine (GalN)- and lipopolysaccharide (LPS)-induced liver injury was investigated. Using the multiple indicator dilution technique, we measured the volume of the hepatic sinusoids and the apparent Disse space as indicators of overall hepatic microcirculation. Serum purine nucleoside phosphorylase activity as a marker of damage to nonparenchymal cells increased and the volume of the sinusoids and the Disse space decreased prior to hepatocyte damage in rats treated intraperitoneally with GalN and LPS. Moreover, the amount of ET-1 release was elevated. When livers from untreated rats were perfused with ET-1 in a recirculating system, hepatocyte damage was observed similar to experiments with GalN and LPS. A monoclonal anti-endothelin antibody, AwETN40, diminished the extent of liver injury caused by GalN and LPS in isolated perfused rat liver. The present study suggests that vasoconstriction is an early event in GalN- and LPS-induced liver injury and that the development of hepatocyte damage is mediated via microcirculatory disturbances due to endogenous ET-1.

Alanine Transaminase↗
PubMed1992

Potent antitumour activity of (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114R) against advanced L1210 leukaemia in mice.

The time dependency of the antitumour activity of (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) monohydrate (DWA2114R) was examined in mice inoculated i.p. with 10(5) mouse L1210 leukaemia cells. The increase in life span was greater in mice treated with 72 mg kg-1 DWA2114R on the 6th day following tumour inoculation than in mice treated at earlier times. Such superior effects against advanced L1210 were also seen with cis-diammine (1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) but not seen with the parent compound, cis-diamminedichloroplatinum(II) (CDDP) or other antitumour agents devoid of platinum. After the injection of DWA2114R on day 6, most of the ascites tumour cells accumulated in the S and G2/M phases of the cell cycle and the total cell number markedly decreased from 10(8) to less than 10(6). On the other hand, only a temporary G1 arrest and a less than 50% reduction of the cell number were induced after a similar treatment on day 3. Interestingly, the superiority of DWA2114R for advanced L1210 was lost in athymic nude mice and mice depleted of T cells by anti-thymocyte antisera. In addition, mice cured of advanced L1210 specifically rejected re-inoculated L1210 cells. These results indicate that the superior antitumour activity against advanced L1210 is unique to DWA2114R among the agents tested (except for CBDCA) and is caused by both an increased drug susceptibility of tumour cells and a drug-induced antitumour effect mediated by T cells of the host mice.

Animals↗
PubMed1992

Antitumor activity and cellular accumulation of a new platinum complex, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)platinum( II) monohydrate, in cisplatin-sensitive and -resistant murine P388 leukemia cells.

We have examined the cytotoxicity and accumulation of (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) monohydrate (DWA2114R) in parent and cisplatin-resistant mouse P388 leukemia cells (P388 and P388/DDP), in comparison with those of cisplatin (CDDP) and carboplatin (CBDCA). The degrees of resistance to CDDP and CBDCA, expressed as the ratio of IC50 for P388/DDP cells to IC50 for P388 cells, were 75-33 and 100-27, respectively, under the conditions of 2-24 h exposure to each drug at a density of 10(6) cells/ml. The corresponding values (25-7) for DWA2114R were relatively low. Accumulations of CDDP and CBDCA were reduced in P388/DDP cells; however, no reduction in accumulation of DWA2114R was observed at various exposure periods and concentrations of the drugs. The accumulations of CDDP in P388 and P388/DDP cells at drug concentrations corresponding to the IC50 values for drug exposure periods of 2-24 h were 0.41-0.97 and 13.1-33.7 ng Pt/10(7) cells, respectively, suggesting that an intracellular mechanism of resistance against CDDP could be activated in P388/DDP cells. P388/DDP cells also showed relatively low resistance to DWA2114R via this mechanism in comparison with CDDP and CBDCA. From the relationship between structure and activity of several Pt-complexes, these different properties of DWA2114R compared with CDDP and CBDCA could be due not only to the differences in carrier ligand structure but also to the properties of the whole molecule associated with the carrier ligand and leaving group.

Animals↗
PubMed1992

[Growth rate of hepatocellular carcinoma and nutritional state].

To clarify the relationship between the growth rate of hepatocellular carcinoma (HCC) and nutritional state or liver function 32 HCC patients with a tumor volume less than 100 ml at the beginning of the study were investigated. These patients all had been treated by serial transcatheter arterial embolization (TAE). Tumor volume was measured by integrating the CT images of the liver before each TAE. The tumor at the TAE just before significant enlargement occurred was defined as the stage I tumor and it was designated stage II at the next TAE. The growth rate of the HCC was then calculated from the tumor volume at stage II minus that at stage I. Caloric intake, protein intake, liver function, and serum amino acid were determined in the patients at each stage. The results were as follows: 1) The tumor growth rate was greater in patients whose caloric intake and protein intake were more than 35 kcal/kg/day and 1.5 g/kg/day, respectively. 2) In patients with the greater tumor growth rate, the plasma BCAA/AAA ratio was the lower. However, after tumor growth, the ratio became higher, indicating that the growth of HCC decreased the requirement of BCAA. 3) The tumor growth rate correlated to the change of plasma arginine level (r = -0.76, p less than 0.05).

Amino Acids↗
PubMed1992

[Effect of treatment schedule of an antitumor platinum complex, DWA2114R, on the antitumor activity].

Effects of treatment schedule of (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato) platinum (II) monohydrate, DWA2114R, on the antitumor activity against murine colon adenocarcinoma (Colon 26) and Lewis lung carcinoma (3LL) were examined. Colon 26 or 3LL tumors were transplanted s.c. into the flank and subsequently DW A2114R was given i.v. by single or multiple injections. The tumor weight was determined on days 14 or 25 and the antitumor effect was evaluated by GIR%. Although the total dose of DWA2114R was identical in both schedules, single injection was superior to multiple. Effect of treatment schedule of cis-dichlorodiammine-platinum (II), CDDP, and cis-diammine (1, 1-cyclobutanedicarboxylato) platinum (II), CBDCA, on the antitumor activities were the same as in case of DWA 2114R, i.e., single injection was superior to multiple.

Animals↗
PubMed1992

[Combination therapy of a new platinum complex, DWA2114R with various antitumor agents against mouse tumors in vivo].

In vivo antitumor activity of (-)-(R)-2-aminomethylpyrrolidine (1, 1-cyclobutanedicarboxylato) platinum (II) monohydrate (DWA2114R) in combination with various antitumor agents was examined using mouse leukemia P388, Meth-A fibrosarcoma and M5076 reticulum cell sarcoma. The combination treatment of DWA2114R with cyclophosphamide, 5-fluorouracil, adriamycin, etoposide or vindesine showed synergistic effects on the prolongation of survival time of mice bearing P388. Among these combinations, combination of DWA2114R with adriamycin or vindesine showed a good synergism. In the combination treatment with vindesine against Meth-A which is not so sensitive to platinum agent, DWA2114R showed a synergistic or additive effect, but cis-diamminedichloroplatinum (II) (CDDP) showed subadditive. Three-drug combination of DWA2114R or CDDP with cyclophosphamide and adriamycin was examined in mice inoculated i.p. or s.c. with M5076. In both models, the combination of DWA2114R was more active than that of CDDP at the dose less than 1/16-fold of the dose of CDDP which is the ratio of two drugs in clinical trial.

Animals↗
PubMed1991

Synthesis, antitumor activity, and nephrotoxicity of the optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)platinum(II).

The optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane- dicarboxylato)platinum(II) (DWA2114, 1), which has potent antitumor activity against various tumors, were synthesized. They were examined for antitumor activity against Colon 26 carcinoma in a sc-iv system, and changes in urinary protein and sugar levels in drug-treated mice were used as an index of nephrotoxicity. In their effect on tumors, (+)-(S)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) (6b) was more potent than the enantiomer 6a in that the effective dose of 6b was smaller than that of 6a; but, both drugs exhibited potent antitumor activity. On the other hand, a distinct difference between 6a and 6b was shown in their nephrotoxicity. Isomer 6b induced a great increase in urinary protein and sugar levels in mice, whereas 6a caused no increase in these levels.

Animals↗
PubMed1991

Comparison of the antitumour effects and nephrotoxicity-inducing activities of two new platinum complexes, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato+ ++)-platinum (II) monohydrate, and its enantiomeric isomer.

New platinum complexes, (-)-(R)-2-aminomethylpyrrolidine(1,1- cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114R) and its enantiomeric isomer, (+)-(S)-2-aminomethylpyrrolidine(1,1- cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114S), were compared in their antitumour effects and nephrotoxicity-inducing activities. Both compounds were effective against the murine tumours L1210 and Colon 26 by i.p. injection of 20-100 mg kg-1. While DWA2114S showed marked increases in blood urea nitrogen (BUN) and urinary protein and sugar in BDF1 mice treated i.p. at the maximum tolerated dose, DWA2114R showed no increases in these parameters. To clarify the difference of nephrotoxicity between the isomers, tissue distribution was examined. Renal Pt concentration in DWA2114S-treated mice was more than 5-fold higher compared with that in DWA2114R-treated mice 2h after i.p. injection of 80 mg kg-1. However, there were no such marked differences in the lung, liver, heart, spleen and plasma. The low content of Pt in the kidneys of DWA2114R-treated mice could explain its lower nephrotoxicity. The in vitro experiments for uptake of the drugs into the cultured normal rat kidney cells and fresh splenocytes revealed that the Pt amount in the cells treated with DWA2114S, especially in the kidney cells, was much higher than DWA2114R.

Animals↗
PubMed1991

Toxicological and tumoricidal evaluations of a new platinum complex, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato+ ++)platinum( II) monohydrate, in rats.

The toxicities and antitumor activity of a new anticancer platinum compound, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +) platinum(II) monohydrate (DWA2114R), were examined in rats by single intravenous injection in comparison with those of cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP). The lethal dose (LD) of DWA2114R (100 mg/kg) or CBDCA (80 mg/kg) caused a slight decrease in body weight (less than 10%) and no significant change in the levels of blood urea nitrogen and urinary sugar and protein. In contrast, a sub-LD level of CDDP (8 mg/kg) seriously decreased body weight (20%) and markedly elevated the levels of these nephrotoxicity parameters. Monitoring the numbers of peripheral blood cells for 3 weeks after the drug injection revealed that all three drugs showed severe thrombocytopenia, moderate leukopenia and slight anemia. However, CBDCA induced the most severe thrombocytopenia among these drugs. The number of platelets was reduced by 60% in rats injected with a half LD of CBDCA. A moderate reduction in platelet count (35-43%) was caused by an equitoxic dose of DWA2114R or CDDP, but abated about 3 days faster than that caused by CBDCA. Interestingly, only CDDP caused an irreversible anemia. Each drug showed a potent antitumor activity at weakly toxic doses against Walker 256 carcinosarcoma transplanted intramuscularly into rats. These results indicate that DWA2114R could be a promising new platinum anticancer agent with an improved toxicity profile.

Animals↗
PubMed1991

Importance of measuring plasma thrombin-antithrombin III complex levels when using antithrombin III concentrate therapy in fulminant hepatic failure.

We investigated changes in the concentrations of thrombin-antithrombin III complex (TAT) and plasmin-alpha 2 plasmin inhibitor complex (PIC) after the intravenous administration of 4000 units of antithrombin III (AT III) concentrate to patients with fulminant hepatic failure (FHF), subacute hepatitis (SH), or liver cirrhosis (LC). FHF patients showed shortening of the initial half-life of exogenous AT III. In addition, a marked rise in plasma TAT was noted 3 to 6 h after the intravenous administration of AT III, even in patients who had a normal plasma TAT level before AT III therapy. In contrast, SH and LC patients showed no marked changes of plasma TAT levels after AT III administration. No marked changes were observed in the PIC concentration in any of the patients. These findings suggest that thrombin formation is increased in FHF and that simple measurement of the plasma TAT concentration is not an adequate method for assessing thrombin formation in FHF patients who have suspected disseminated intravascular coagulation associated with an apparent decrease in AT III synthesis. Instead, it seems necessary to measure the plasma TAT concentration in FHF patients after replacement therapy with AT III concentrate has been performed, to evaluate their hypercoagulability more accurately.

Adult↗
PubMed1991

[A case of suicide suspected of poisoning from taking some agricultural chemicals].

Forensic toxicological examination was performed on a person who was suspected of poisoning by Azomite emulsion (an acaricide), Roundup (a herbicide) and/or unidentified agricultural chemical and died after 4 days. In Japan, production of Azomite emulsion has been stopped since 1973. The unidentified agricultural chemical was identified as an agricultural chemical containing malathion, an organo phosphorous compound, by analyzing with gas chromatograph-mass spectrometer (GC-MS). When the person's serum was qualitatively analyzed with GC-MS, aramite and azoxybenzene, effective components of Azomite emulsion, were detected but not glyphosate, effective component of Roundup, and malathion. And so, quantitative analysis of aramite and azoxybenzene were performed with mass fragmentography. Aramite and azoxybenzene concentrations in the serum obtained at about 9 hours after he took Azomite emulsion were 5.20 micrograms/ml and 112 micrograms/ml, respectively. Only trace amounts of them were, however, detected in the serum obtained at about 3.5 days after that. Both aramite and azoxybenzene existed significantly in liver of the corpse, and their concentrations were 12.0 micrograms/g and 254 micrograms/g, respectively. Relatively large amounts of them were also deposited in the kidney. Severe liver and kidney disorders shown in this case were considered to be mainly induced by deposits of aramite and azoxybenzene in the liver and kidney. Also in the future, poisoning by agricultural chemicals that productions have been stopped like Azomite emulsion may happen. Therefore, it may be necessary for forensic toxicologists and medical doctors in emergency hospitals to try to be able to cope promptly with such poisoning cases.

Agrochemicals↗
PubMed1990

Synthesis and antitumor activities of platinum complexes of unsymmetrical alicyclic diamines as carrier ligands.

The synthesis and biological activities of the platinum complexes of 2-aminomethylaziridine, 2-aminomethylazetidine, 2-aminomethylpyrrolidine, 2-aminomethylpiperidine as carrier ligands are described. The platinum complexes of 2-aminomethylazetidine and 2-aminomethylpyrrolidine are significantly effective against murine tumors. In particular, 2-aminomethylazetidine (1,1-cyclobutanedicarboxylato)platinum II (13) and 2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)platin um II (16) exhibited potent antitumor activity and were soluble in water, and their antitumor activities against Colon 26 carcinoma (sc-ip system) were superior to CBDCA and comparable to CDDP.

Animals↗
PubMed1990

Lectin-reactive profiles of alpha-fetoprotein characterizing hepatocellular carcinoma and related conditions.

Serum alpha-fetoprotein from 146 patients with hepatocellular carcinoma, other malignancies, and benign liver diseases, was fractionated by lectin-affinity electrophoresis coupled with our sensitive detection method of antibody-affinity blotting. Compared with chronic hepatitis and liver cirrhosis, hepatocellular carcinoma was characterized by the increase in proportions of lentil lectin A-reactive alpha-fetoprotein-L3 and erythroagglutinating phytohemagglutinin-reactive alpha-fetoprotein-P4; the yolk sac tumor was characterized by the increase of concanavalin A-nonreactive alpha-fetoprotein-C1, lentil lectin-A-weakly reactive alpha-fetoprotein-L2, erythroagglutinating phytohemagglutinin-strongly reactive alpha-fetoprotein-P5, and Allomyrina dichotoma lectin-nonreactive, slow-migrating alpha-fetoprotein-Als; and gastrointestinal tumors were characterized by alpha-fetoprotein-C1, alpha-fetoprotein-L2, alpha-fetoprotein-L3, alpha-fetoprotein-P5 and Allomyrina dichotoma-nonreactive alpha-fetoprotein-A1. By combined evaluation of alpha-fetoprotein-L3 and alpha-fetoprotein-P4, hepatocellular carcinoma was discriminated from chronic hepatitis and liver cirrhosis with a sensitivity of 97% at a specificity of 99.7%. Because the alpha-fetoprotein level of the studied cases ranged from 60-1,500,000 ng/mL (60-1,500,000 micrograms/L), mostly greater than 200 ng/mL (200 micrograms/L), additional patients with lower levels of alpha-fetoprotein [16-177 ng/mL (16-177 micrograms/L) for 16 cases of hepatocellular carcinoma with liver cirrhosis and 28-185 ng/mL (28-185 micrograms/L) for 17 cases of liver cirrhosis alone] were analyzed for alpha-fetoprotein-L3 and alpha-fetoprotein-P4. The resulting sensitivity for combined evaluation was still as high as 88% at the same high specificity of 99.7%, indicating that the simultaneous analysis of alpha-fetoprotein-L3 and alpha-fetoprotein-P4 is effective in monitoring the evolution of hepatocellular carcinoma in cirrhotic patients.

Adult↗
PubMed1990

Effect of recombinant human erythropoietin on anticancer drug-induced anaemia.

Anaemia was induced in rats with fluorouracil (5-FU) or cisplatin (CDDP) and the mechanisms of anaemia induction were analysed. Furthermore, the therapeutic effects of recombinant human erythropoietin (rHu Epo) on these anticancer drug-induced anaemias were investigated. In 5-FU-induced anaemia, marked serum erythropoietin (Epo) elevation was observed in inverse correlation to blood Hb concentration and Hb concentration rapidly recovered to normal levels. On the other hand, in CDDP-induced anaemia, serum Epo elevation was modest and the lowered Hb concentration persisted longer. Treatment with rHu Epo significantly improved both anticancer drug-induced anaemias but rHu Epo was more effective on CDDP-induced anaemia. These results suggest that rHu Epo might be useful for the therapy of anaemia associated with anticancer chemotherapy.

Anemia↗
PubMed1990

Filtration of fresh frozen plasma used as substitution fluid in plasma exchange in order to remove microaggregates.

Freshly melted fresh frozen plasma (FFP) contains a large number of particles smaller than 20 microns in diameter. These particulate materials (microaggregates) consist of aggregated triglyceride-rich lipoproteins (LA) and precipitable aggregates closely resembling fibrin (FA). Both LA and FA injected into a rat's tail vein were trapped in the lung and formed emboli in the pulmonary arterioles. To prevent the passage of these microaggregates into the systemic circulation, a new circuit was devised for plasma exchange containing a filter with a pore size of 0.2 microns. In 17 patients with fulminant hepatitis who received plasma exchange transfusions and subsequently died and were autopsied, the incidence of pulmonary complications was significantly lower in the 12 patients who received filtered FFP. According to these results, the possibility of pulmonary complications due to micro-embolism developed by microaggregates in FFP should be taken into account when a large amount of FFP is repeatedly infused into critically ill patients.

Animals↗
PubMed1990

Synthesis of platinum complexes of 2-aminomethylpyrrolidine derivatives for use as carrier ligands and their antitumor activities.

In order to study a new antitumor platinum complex, various platinum complexes were prepared from 2-amino-methylpyrrolidine derivatives synthesized to serve as carrier ligands and tested for their antitumor activity against Colon 26 carcinoma (s.c.-i.p. system) and P388 leukemia (i.p.-i.p. system) in mice. 2-Aminomethylpyrrolidine proved to be the most effective carrier ligand in its amine derivatives. The structure-activity relationships of the carrier ligands in the platinum complexes with dichloro, oxalato, 1,1-cyclobutanedicarboxylato and dichlorodihydroxo as leaving group were clearly shown on the Colon 26 carcinoma screen and were as follows: the antitumor activity of the platinum complexes with any leaving groups was considerably decreased by the substitution of hydrogen by alkyl group (Me, Et) on nitrogen of aminomethyl and the effects of 1,1-cyclobutanedicarboxylato Pt(II) complexes completely disappeared with the same substitution on nitrogen of pyrrolidine. In all the tested platinum complexes 2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)platin um(II) (15) exhibited the most potent antitumor activity. 15 was superior to 1,1-cyclobutanedicarboxylatodiammineplatinum(II) (CBDCA) and similar to cis-diamminedichloroplatinum(II) (CDDP) on the Colon 26 carcinoma screen but it was inferior to CBDCA and CDDP on the P388 leukemia screen. Furthermore, 15 showed more potent antitumor activity than CBDCA against Colon 38 carcinoma (s.c.-i.p. system).

Animals↗