Biomedical subjects
Publications and source records attributed to M Arai.
The effect of acute administration of ethanol on endotoxin-induced liver injury was studied. Biochemical and histological results indicated that ethanol pretreatment protected endotoxin-induced liver injury through the improvement of hepatic blood circulation, which is probably associated with an inhibitory effect of ethanol on platelet functions and coagulation system.
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The gene encoding a proteinous alpha-amylase inhibitor (HaimII) of Streptomyces griseosporeus YM-25 has been cloned in Escherichia coli K12 using a deoxyinosine-containing synthetic oligonucleotide as the probe. A 1.6 kilobases BamHI fragment was confirmed to hybridize with the probe and subcloned in an E. coli-S. lividans shuttle vector. The plasmid clone was transferred into S. lividans by transformation. An appreciable amount of alpha-amylase inhibitor activity was found in the culture medium of S. lividans harboring the plasmid. As the specificity was indistinguishable from that of HaimII produced by the original S. griseosporeus strain, we concluded that the HaimII protein was synthesized in S. lividans and excreted into the medium.
CS-514 is a tissue-selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a key enzyme in cholesterol synthesis. For the microsomal enzyme from rat liver, the mode of inhibition is competitive with respect to hydroxymethylglutaryl-CoA, and the Ki value is 2.3 X 10(-9) M. CS-514 also strongly inhibited the sterol synthesis from [14C]acetate in cell-free enzyme systems from rat liver and in freshly isolated rat hepatocytes; the concentrations required for 50% inhibition were 0.8 ng/ml and 2.2 ng/ml, respectively. On the other hand, the inhibition by CS-514 was much less in the cells from nonhepatic tissues such as freshly isolated rat spleen cells, and cultured mouse L cells and human skin fibroblasts. In addition, the cellular uptake of 14C-labeled CS-514 by isolated rat spleen cells or mouse L cells was less than one-tenth of that by isolated hepatocytes. These differences between hepatic and nonhepatic cells were further confirmed by the fact that CS-514 orally administered to rats inhibited sterol synthesis selectively in liver and intestine, the major sites of cholesterogenesis. CS-514 markedly reduced serum cholesterol levels in dogs, monkeys and rabbits, including Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia in man, but did not reduce those in rats and mice. In the former case, preferential lowering of atherogenic lipoproteins was observed in all of the animals tested. The biliary neutral sterols significantly decreased, whereas the amount of biliary bile acids was not affected by administration of the drug to dogs.
The effects of delta 8-tetrahydrocannabinol (delta 8-THC) and its major and active metabolite, 11-hydroxy-delta 8-tetrahydrocannabinol (11-OH-delta 8-THC), on the hepatic microsomal drug-metabolizing enzyme system were studied in mice. The repeated administration of 11-OH-delta 8-THC (5 mg/kg/day, i.v.) for 3 or 7 days increased significantly the activities of aniline hydroxylase and p-nitroanisole O-demethylase. By the same treatment, cytochrome P-450 content (3 days) or NADPH-cytochrome c reductase activity (7 days) was also increased significantly. The treatment with delta 8-THC for 7 days (5 mg/kg/day, i.v.) significantly increased aniline hydroxylase only. 11-OH-delta 8-THC increased the Vmax, but not the Km, values for both drug-metabolizing enzymes, whereas delta 8-THC decreases significantly the Km value (270 microM) for p-nitroanisole O-demethylase as compared with the control (398 microM). Repeated administration of these cannabinoids for 7 days also increased the metabolism of delta 8-THC by hepatic microsomes; this was attributed to an enhanced formation of 11-OH-delta 8-THC. In contrast, microsomal formation of 7 alpha-OH-delta 8-THC was decreased significantly by treatment with delta 8-THC. 11-OH-delta 8-THC, but not delta 8-THC, treatment increased the metabolism of 11-OH-delta 8-THC by hepatic microsomes. These findings indicate that delta 8-THC and 11-OH-delta 8-THC treatment can induce hepatic microsomal drug-metabolizing enzymes and affect differently the catalytic properties of the enzymes.
Early diagnosis of lung fibrosis has been hampered by the lack of a simple, convenient and specific test. Measurement of serum type III procollagen peptide (Pro (III)-N-P) by the method originally developed by Rohde et al. has been shown to be useful for the evaluation of hepatic fibrosis. The present study, therefore, was carried out to investigate the usefulness of the measurement of Pro (III)-N-P in 24 patients with lung fibrosis due to silicosis, and in 7 patients with malignant lymphoma treated with bleomycin, antitumor antibiotic which has the adverse effect of producing fibrosis in the lung. The normal value of the peptide in adults was 8.60 +/- 2.35 ng/ml (mean +/- SD; n = 68) and the normal upper level was set at 13.4 ng/ml (mean +/- 2SD). Patients with silicosis had significantly but not extremely high levels of the peptide and 25% of the patients showed abnormally high values. The level of Pro (III)-N-P was associated with neither physical findings, chest X-p findings nor pulmonary function test results. Three of 7 patients showed increased levels during treatment with bleomycin. In one case, a total dose of 120 mg of bleomycin for over a period of 14 months markedly increased the level of the peptide. These observations suggest that the determination of Pro (III)-N-P may be useful for the detection of lung fibrosis.
We have investigated the effect of nifedipine on acetylcholine-induced bronchoconstriction in 8 asthmatics and on histamine-induced bronchoconstriction in another 8 asthmatics on a single-blind basis. Expiratory spirograms were done at the beginning of the examination in all subjects, and repeated after 10 mg of oral nifedipine or a placebo. The change of respiratory resistance during the inhalation of acetylcholine or histamine was recorded continuously by an Astograph. Using this device, we were able to obtain the direct-writing dose-response curve of respiratory resistance measured during quiet breathing. Resting airway tone appeared to be generally unaffected by nifedipine, as there was no significant change in baseline spirograms. Nifedipine increased significantly the threshold of bronchial responsiveness, i.e., the cumulative dose of acetylcholine (Dmin) at which the respiratory resistance started to increase, compared with placebo (p less than 0.02). However, Sd, the slope of the increasing rate of respiratory resistance in the dose-response curve, was not attenuated by nifedipine. In histamine inhalation tests, neither Dmin nor Sd were modified by nifedipine. The discrepancy observed between the effects of nifedipine on acetylcholine- and histamine-induced bronchoconstriction may imply that, in asthmatics, nifedipine exerts its effect mainly by stabilizing mast cells rather than by directly inhibiting bronchial smooth muscle contractility. This hypothesis is based on the fact that mast cells have acetylcholine receptors on their surfaces but no histamine H1-receptors.
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To study the effects of chronic alcohol consumption on platelet functions, the rate of arachidonate-induced platelet aggregation, the production of malondialdehyde in platelets, and plasma levels of prostaglandin endoperoxide metabolites were examined in 88 chronic alcoholics and 24 healthy controls. The rate of platelet aggregation and the production of malondialdehyde in platelets were greater in chronic alcoholics both on admission and 1 week after. However, these alterations returned to the level of healthy controls within 4 weeks of abstinence from alcohol and were independent of the number of circulating platelets. Furthermore, on admission, plasma levels of thromboxane B2 were significantly increased in chronic alcoholics when compared with those of healthy controls (400.8 +/- 36.5 versus 241.7 +/- 28.9 pg/ml plasma; p less than 0.025) and were also significantly correlated with malondialdehyde production in washed platelet debris (r = 0.6049; p less than 0.001). In contrast, plasma levels of 6-keto prostaglandin F1 alpha and prostaglandin E were not altered after chronic alcohol consumption. As a result, the ratio of 6-keto prostaglandin F1 alpha to thromboxane B2 was markedly decreased in chronic alcoholics (0.31 +/- 0.03 versus 0.62 +/- 0.13; p less than 0.001). These results strongly suggest that the imbalance in prostaglandin endoperoxide metabolites is produced by chronic alcohol ingestion. Moreover, a significant correlation was observed between platelet aggregation rate and malondialdehyde production during platelet aggregation (r = 0.559; p less than 0.005). Thus, we conclude that chronic alcohol consumption alters platelet thromboxane metabolism, which is likely associated with the increased ability of platelets to aggregate.
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A 52-year-old man with a three-month history of left epigastralgia and body weight loss was referred to us for a possible abdominal tumor in March 1984. Retroperitoneal malignant tumor was suspected by ERCP, angiography, US, and CT. At laparotomy, a child's-head-sized retroperitoneal tumor, which weighed 1,800 g, was resected. Pathological examination revealed the diagnosis of retroperitoneal malignant fibrous histiocytoma (MFH). He died because of recurrence in the retroperitoneum six months after the operation. We selected 26 Japanese cases of retroperitoneal MFH and discussed their clinical findings and prognosis.
To test the effectiveness of cefmenoxime (CMX) and cefotiam (CTM) in patients with biliary tract diseases, concentrations of either antibiotic were measured after an intravenous bolus injection of 1.0 g of CMX or CTM, or simultaneous injection of both (1.0 g each). CMX or CTM was injected in 76 patients with biliary tract diseases (mostly cholelithiasis) prior to a cholecystectomy and concentrations of CMX or CTM were measured by the bioassay (agar well) method at 30 to 60 minutes after the injection. Average concentrations of both CMX and CTM in gallbladder bile and gallbladder tissue sufficiently exceeded the minimal inhibitory concentration (MIC) against main causative organisms of biliary tract infections. Concentrations of both antibiotics in gallbladder bile were significantly higher in patients with patent cystic ducts than with obstructed cystic ducts. Concentrations of both antibiotics in the gallbladder tissue reached at a similar high level regardless of the patency of the cystic ducts, but concentrations were lower in severely inflamed gallbladders. CMX and CTM were administered alternatively (cross-over fashion), or simultaneously (combined) to 13 patients with T-tube drainage or percutaneous transhepatic cholangio-drainage, and concentrations of both antibiotics in bile from the drainage tube were measured by high performance liquid chromatography at hourly intervals after the injection. Concentrations of both antibiotics were far greater than MICs against main attributable microorganisms in biliary tract infections. The concentration of CMX slightly exceeded that of CTM. Concentrations of both antibiotics were lower in bile of patients showing abnormally high serum GTP, A1-P, and total bilirubin levels than in bile of patients with normal values of these variables. It is speculated that the secretion of both antibiotics in the bile may decrease in cases with severe hepatic failure, but effective concentrations of both antibiotics in the gallbladder tissue should be maintained as long as the blood circulation in the gallbladder was maintained.
To patients with chronic complicated urinary tract infections (UTI) which were in compliance to the UTI standard, cefmenoxime (CMX) was given singly or in combination with cefsulodin (CFS) and efficacies of the respective preparations were examined. Of 53 patients examined, 40 were given CMX alone while 13 were given a combined preparation of CMX and CFS. Results are summarized as follows. With respect to the general clinical effects, 7 patients given CMX alone were markedly improved, 21 improved and 12 unchanged indicating an efficacy rate of 70%. In case of the CMX-CFS combined administration, 2 patients were markedly improved, 7 improved and 4 unchanged giving an efficacy rate of 69%. As for the bacteriological effects, 38 of 54 strains isolated from the patients given CMX alone were eliminated, 4 decreased, 12 unchanged and 15 substituted. Of 16 strains isolated from the patients given the CMX-CFS combined preparation, 4 were eliminated, 2 unchanged and 3 substituted. Thus, incidence of bacterial substitution was low in the combination treatment. The combination of CMX and CFS was more inhibitory to P. aeruginosa than CMX alone. Regarding side-effects, drug eruption was observed in one of the 53 patients and slight elevation of GOT and GPT was recognized in another.