Biomedical subjects

K Endoh

Publications and source records attributed to K Endoh.

At least 73 records · Page 4Linked to original sources

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

Mechanism of intragastric nicotine protection against ethanol-induced gastric injury.

To elucidate the mechanism of intragastric nicotine protection against ethanol-induced gastric mucosal injury seen in a previous report and in our preliminary study, the following studies were performed. Rats were pretreated with naloxone (8 mg/kg intraperitoneal, 0.5 hr prior to study) to block opiate receptors; or capsaicin (125 mg/kg subcutaneous 10 days prior to study) to denervate the afferent sensory fibers; or indomethacin (2.5 mg/kg intragastric or 5 mg/kg subcutaneous, 1 hr prior to study) to inhibit endogenous prostaglandin synthesis. At 1-hr intervals, nicotine (4 mg/kg) or vehicle and 40% ethanol were then given intragastrically. Total gastric corpus mucosal lesion length was measured unbiasedly. In separate studies, gastric mucosal blood flow (GMBF) was assessed by hydrogen gas clearance before and after intragastric nicotine or vehicle; luminal mucus volume, gastric juice volume, and acid output were measured 1 hr after either intragastric nicotine or vehicle administration. The results showed that the acute protective effect of intragastric nicotine was associated with a significantly larger luminal mucus volume. It was not blocked by naloxone, capsaicin, or indomethacin. There was no increase in GMBF. The larger gastric residual volume did not account for the protection. We conclude that the mechanism mediating nicotine protection is unique and is independent of opiate receptors, capsaicin-sensitive afferent sensory nerve fibers, endogenous prostaglandin generation, or dilution of the injurious agent. The increase in luminal gastric mucus volume may contribute to the protective effect of intragastric nicotine against gastric mucosal injury produced by 40% ethanol.

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

A simulation study of physiological factors affecting pharmacokinetic behaviour of organic solvent vapours.

At a given external dose of an inhaled chemical the internal dose or the amount absorbed into the body varies depending on pulmonary ventilation and other physiological factors. Such variability is of concern in the development of biological indices of occupational exposure to organic solvent vapours. This paper discusses how physiological factors may influence the pharmacokinetic behaviour of inhaled organic solvent vapours, especially in relation to monitoring of biological exposure. To illustrate the discussion a computer based physiological pharmacokinetic model was used describing quantitatively the influence of body size, body fat content, and sex on the pharmacokinetic behaviour of trichloroethylene. Absorption, distribution, metabolism and excretion of trichloroethylene were found to vary according to the different anatomical features of men and women. Body build (body weight and body fat content) also affected the pharmacokinetic behaviour of this solvent.

Body Constitution↗

PubMed1991

Effects of consumption of ethanol on the biological monitoring of exposure to organic solvent vapours: a simulation study with trichloroethylene.

This study illustrates possible influences of consumption of ethanol on the pharmacokinetic behaviour of inhaled trichloroethylene (TRI) in relation to biological monitoring of exposure. The results were obtained for a standard male worker of 70 kg by physiologically based pharmacokinetic modelling. Depending on the pattern of consumption of ethanol, enzyme inhibition or induction was assumed to prevail in this worker. The inhibition and induction were modelled by assuming competitive metabolic interaction between TRI and ethanol and increased maximum velocity (Vmax) of TRI metabolism respectively. Ingestion of moderate amounts of ethanol before the start of work or at lunch time, but not at the end of work, caused pronounced increases in blood TRI concentrations and decreases in the urinary excretion rates of TRI metabolites, this effect lasting until the next day. The effects were smaller the higher the exposure concentration of TRI. Induction of TRI metabolism, supposedly by consumption of ethanol the previous evening, caused only small changes in the pharmacokinetic profile at 50 ppm, but appreciable changes at 500 ppm.

Alcohol Drinking↗

PubMed1991

Mechanism of aggravation of mucosal injury by intravenous nicotine in rat stomach.

Endogenous prostaglandins and injury-induced hyperemia are important defense mechanisms in the gastric mucosa. In the rat stomach, we tested the hypotheses that an ulcer-promoting dose of intravenous nicotine 1) reduces ex vivo prostaglandin generation and 2) aggravates mucosal lesions by impairing injury-induced hyperemia. Anesthetized rats were given intravenous control or 4 or 40 micrograms.kg-1.min-1 nicotine infusion. In study 1, ex vivo generation of prostaglandin E2 and 6-ketoprostaglandin F1 alpha (stable metabolite of prostacyclin) was determined by vortexing the mucosal tissue, followed by radioimmunoassay. No significant difference in prostaglandin generation was found between the control and experimental groups. In study 2, intravenous nicotine (40 micrograms.kg-1.min-1) produced a significant rise (19 +/- 3%) in mean blood pressure and completely abolished the gastric hyperemia produced by intragastric saline (2 M). The extent of the associated gastric mucosal injury was significantly increased (from 5.3 +/- 0.8 to 17.4 +/- 5.2% of the corpus mucosa), while the maximum depth of the largest lesions was not affected by intravenous nicotine. The data confirm that the gastric hyperemia associated with gastric mucosal exposure to hypertonic saline plays an important role in limiting the extent of gastric mucosal damage. We conclude that in the rat stomach 1) an ulcer-promoting dose of intravenous nicotine does not significantly inhibit cyclooxygenase activity, and 2) the same does of intravenous nicotine exacerbates hypertonic saline-induced gastric mucosal injury by a mechanism that involves inhibition of injury-induced hyperemia.

6-Ketoprostaglandin F1 alpha↗

PubMed1991

[Physiological and environmental factors affecting biological monitoring of exposure to organic solvent vapors].

A review of the literature was made on the physiological and environmental factors affecting pharmacokinetic behavior of organic solvent vapors in relation to biological monitoring of exposure to organic solvents. Among the physiological factors the importance is attached to body build (body weight and body fat content), sex, and physical activity. Environmental factors are centered on cigarette smoking, medications, coexistence of other solvents, dietary intake, and ethanol consumption with special emphasis of their effects on the hepatic metabolism of organic solvents.

Animals↗

PubMed1991

Cytogenetic analysis of human bile for mutagenicity and co-mutagenicity.

Cytogenetic analysis was used to test whether or not human bile induced chromosome abnormalities in lymphocytes grown in culture. Bile was obtained from gallbladders resected for various reasons such as cholecystitis, cholelithiasis, polypus and cancers of the biliary tract, stomach and pancreas. After adding human bile to a final concentration of 25 microliters/ml or 12.5 microliters/ml, the culture medium was incubated at 37 degrees C for 72 hr. Air-dried slides were stained with conventional Giemsa and the numerical and structural chromosome abnormalities were scored. Positive and negative controls in terms of chromosome abnormalities were established by using 0.03 micrograms/ml mitomycin C (MMC) and 0.9% normal saline, respectively. Cytogenetic analysis was successfully performed in 6 out of 10 bile samples (60.0%). Bile alone did not induce numerical or structural chromosome abnormalities. Structural abnormalities increased significantly in the 25 microliters/ml bile + 0.03 micrograms/ml MMC group, compared with the 0.03 micrograms/ml MMC group: 36.0% vs. 20.7% in the chromatid-type gaps and breaks, 27.8% vs. 22.7% in the chromosome-type gaps and breaks, and 8.3% vs. 3.2% in the exchange-type abnormalities. It is likely that the interaction between bile and MMC is synergistic rather than additive.

Adult↗

PubMed1991

[The effect of surfactant therapy associated with high frequency jet ventilation on oxygenation in canine lavaged lungs].

The effects of exogenous surfactant (SF) replacement therapy associated with high frequency jet ventilation (HFJV) on blood gas changes, pulmonary and hemodynamic variables were studied in canine lavaged lungs. The lungs were lavaged repeatedly with physiological saline until PaO2 decreased to 100 mmHg under intravenous pentobarbital anesthesia with 100% oxygen. SF (50 mg.kg-1) in the experimental group (n = 12) and saline in the control group (n = 8) were administered to the trachea using HFJV with a duration of 10 min. HFJV was further continued for 1 hour to make surfactant distribute evenly. Then respiration was controlled by the conventional mechanical ventilator for 3 hrs. During the administration of SF (10 min). PaCO2 was not altered. In the surfactant group, PaO2 improved significantly (200 mmHg) at the end of HFJV and was maintained for the next 3 hrs at this level, but it did not improve in the saline group. Therefore, we suggest that HFJV can be used safely for the treatment of acute respiratory failure and is an effective method for the administration of the pulmonary surfactant into the alveoli.

Animals↗

PubMed1990

Stimulation of calcium mobilization but not proliferation by bombesin and tachykinin neuropeptides in human small cell lung cancer cells.

The tachykinin family of neuropeptides, including substance P and neurokinins A and B, induce a transient increase in intracellular free calcium concentration in human small cell lung carcinoma (SCLC) cells, as measured with a calcium indicator fura-2. The effects are dose dependent and even greater than that of bombesin at equimolar concentrations in these cells. The tachykinins, like bombesin, induce calcium mobilization mainly from intracellular store(s). None of the peptides, however, shows a stimulatory effect on DNA synthesis. In addition, exogenously applied bombesin does not stimulate DNA synthesis at any concentration tested. We also examined the effects of a recently reported bombesin antagonist [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P in SCLC cells, and compared them to those in Swiss 3T3 fibroblasts in which the mitogenic effect of bombesin is well characterized. The antagonist at 10(-5) M completely abolishes the Ca2+-mobilizing effect of 10(-7) M bombesin in SCLC cells, and that of 10(-9) M but not 10(-7) M bombesin in Swiss 3T3 cells. The antagonist at this concentration effectively inhibits the mitogenic action of bombesin (10(-9) M) in Swiss 3T3 cells; however, much higher doses (approximately 10(-4) M) are needed to inhibit DNA synthesis in SCLC cells. Moreover, the antagonist inhibits DNA synthesis in bombesin/gastrin-releasing peptide-nonproducing cells with a similar dose dependency as in producing cells. These results indicate that bombesin/gastrin-releasing peptide and other calcium mobilizing peptides do not always act as a growth factor in SCLC cells, and that the bombesin antagonist could inhibit growth of SCLC cells through a mechanism other than bombesin antagonism.

Bombesin↗

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

Effect of epidermal growth factor in combination with sucralfate or omeprazole on the healing of chronic gastric ulcers in the rat.

Epidermal growth factor (EGF) has been shown to enhance healing of experimental gastric ulcers when given subcutaneously or orally in the drinking water. This effect of EGF occurs without reducing gastric acid secretion. On the other hand, EGF reportedly is excreted rapidly from gastric lumen when administered by intragastric bolus. This suggests that further stimulation of ulcer healing may be expected if EGF is given with an acid-suppressive agent or with an agent allowing EGF to remain in rat gastric lumen at high concentrations. In the present study, EGF administered by gastric intubation at a dose of 10 micrograms/kg, which is three times smaller than reported in previous studies, was evaluated for its effect on acetic acid-induced rat gastric ulcers in combination with sucralfate or omeprazole. Sucralfate is well known selectively to bind proteins covering the ulcer base, and omeprazole is a potent acid-suppressive agent. Prior to the study of combined EGF and sucralfate, oral sucralfate was confirmed to allow endogenous gastric EGF and mouse EGF given exogenously to remain at high concentrations in gastric contents and tissues. EGF and sucralfate (2 g/kg/day) given alone failed to stimulate ulcer healing in submandibularectomized rats (SMR rat) whose endogenous gastric EGF was depleted. However, the combination of both drugs administered at the same doses significantly accelerated ulcer healing in the SMR rat. Omeprazole (200 mg/kg/day) significantly enhanced ulcer healing regardless of removal of the submandibular glands. The combination of EGF and omeprazole further stimulated ulcer healing in the SMR rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗

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

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↗

PubMed1990

HLA antigens in cancer of the gallbladder.

Thirty one patients with gallbladder cancer (GBC) and 32 healthy controls were typed using antisera against 12 HLA-A, 31 HLA-B, 7 HLA-C and 13 HLA-DR antigens. The DR4 frequency of 61.3% (19/31) in GBC was significantly different from that of 28.1% (9/32) in the control (p = 0.00794 by Fisher's exact test). The relative risk and the etiologic fraction were 4.0 and 0.46, respectively.

Adult↗

PubMed1990

[Evaluation of SOD activity in gastric mucosa of hemorrhagic shock rats].

UNLABELLED: Superoxide dismutase (SOD) exogenously administered has been documented to protect gastric mucosa against ischemia-reinfusion injury by scavenging oxygen radicals. However, the changes in levels of endogenous SOD in ischemic gastric mucosa are not known. To evaluate this, the present study was designed. METHODS: Fasted and anesthetized SD rats were given 0.1 N HCl i.g. and received the following procedures. Study 1: (1) Ischemia group--25 min after acid instillation, blood pressure was reduced to 20-30 mmHg for 20 min. (2) Ischemia-Reinfusion group--5 min after acid administration, rats received the same hypotension as above followed by reinfusion of shed blood for 20 min. (3) Control group-Rats were killed 45 min later without hypotension and reinfusion. Study 2: Three groups of rats treated with the same procedures as in Study 1 were given allopurinol (50 mg/kg/day) i.g. once daily for 2 days prior to the experiment. All rats were killed by exsanguination from the carotid artery to avoid as much as possible contamination of gastric mucosal samples with red blood cells rich in SOD. The supernatants of the corpus and antral mucosa homogenized were prepared for measuring their SOD activity using the nitrite method modified by Oyanagui. RESULTS: SOD activity in the gastric mucosa significantly increased in both the Ischemia (Ische.) and Ischemia-Reinfusion (I-R) groups compared to the control (Ische. vs. I-R vs. Cont'l: corpus-123.4 +/- 4.8 vs. 127.4 +/- 3.6 vs. 96.9 +/- 4.4 NU/Mg protein; antrum-71.6 +/- 2.8 vs. 81.4 +/- 6.8 vs. 62.1 +/- 3.1 NU/mg protein). No increase in SOD activity was observed in rats pretreated with allopurinol. CONCLUSION: SOD activity increases with oxyradicals generation in the rat stomach subjected to either hemorrhagic ischemia alone or hemorrhagic ischemia plus reinfusion. This also suggests that oxyradicals are generated even in the ischemic period.

Animals↗

PubMed1989

A sensitive enzyme immunoassay system of rat epidermal growth factor in biological fluids and tissue extracts.

Rat epidermal growth factor was purified from rat submandibular glands to obtain specific antiserum for the establishment of an immunoassay system. Purified rat epidermal growth factor showed a single peak on reverse phase HPLC and a single band on sodium dodecyl sulphate polyacrylamide gel electrophoresis at mol wt 5100 in the presence of 2-mercaptoethanol and at mol wt 41,000 in the absence of 2-mercaptoethanol. Antibody against rat epidermal growth factor showed cross-reactivities with mouse and human epidermal growth factors on soft agar-double immunodiffusion test. The established sandwich enzyme immunoassay for rat epidermal growth factor had a high sensitivity (500 fg/tube), which made it possible to measure minute amounts of endogenous rat epidermal growth factor without pretreatment. Physiological concentrations of rat epidermal growth factor in rat biological fluids and tissues were determined. Species differences in physiological distributions of epidermal growth factor are discussed.

Animals↗

PubMed1989

[A physiologically based pharmacokinetic model to describe the transfer of organic solvents in the human body. Simulation of kinetic behavior of trichloroethylene using a spreadsheet program].

A physiologically based pharmacokinetic model was developed to describe the transfer of organic solvent vapors in the human body. The model was composed of seven tissue compartments, i.e., lungs, vessel-rich tissues, vessel-poor tissues, muscles, fat tissues, gastrointestinal tissues, and liver, each being interconnected by the blood flow system. Transfer of organic solvents was expressed in the form of simultaneous differential equations, which were then solved numerically on a personal computer using a simple spreadsheet program. The simulation of pharmacokinetic behavior of trichloroethylene with this model was found to be in general agreement with the experimental data. The usefulness of a physiological simulation model to elucidate some toxicokinetic aspects of human exposure to organic solvent vapors is discussed.

Computer Simulation↗