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Biomedical subjects

K Fukuhara

Publications and source records attributed to K Fukuhara.

140 records · Page 8Linked to original sources
PubMed1979

Toxicological and teratological studies of 2-chloro-11-(2-dimethylaminoethoxy)-dibenzo[b,f]thiepine (zotepine), a new neuroleptic drug.

Toxicological and teratological studies of 2-chloro-11-(2-dimethylaminoethoxy)dibenzo[b,f]thiepine (zotepine) were performed in mice, rats, rabbits and dogs. There was no essential difference among mice, rats, rabbits and dogs in the acute toxicity of i.v. given zotepine. The rather small variation between intravenous and oral acute toxicity suggests the good absorption of zotepine from the gastrointestinal tract. In the subacute and chronic toxicity studies in rats, significant changes attributed to the drug were impairment of growth, alveolar proliferation in the mammary gland, decrease in uterine weight and increased number of diestrous rats. These changes were dose-dependent in the animals given 16 mg/kg or higher. Incidence of tumor in the treated groups in the 12-month study was almost the same as that in the control. In the subacute and chronic toxicity studies in dogs, abnormal quietness and abnormal gait occurred. Enlarged breasts and galactorrhea also occurred in females given 16 and 64 mg/kg in the 6-month study. Apart from these changes, one dog given 64 mg/kg had reversible hepatic dysfunction. In the teratological studies, zotepine had no adverse effects on pregnant animals and their fetuses in rats and rabbits, or reproductive performance of the F1 rats.

Animals↗
PubMedDate not supplied

Kupffer cell-mediated inhibition of liver regeneration after combined hepatectomy and pancreatectomy.

Recently, simultaneous hepatectomy and pancreatoduodenectomy has been performed for the treatment of some biliary tract cancers in Japan. Postoperative hepatic failure is a common and potentially fatal complication. The aim of this study was to examine the reduction in the rate of liver regeneration after 70% hepatectomy (Hx) alone or in combination with 70% pancreatectomy (HPx). Male Sprague-Dawley rats underwent hepatectomy or simultaneous hepatectomy and pancreatectomy. The ratio of liver weight to body weight, the labeling index of hepatocytes in vivo, and DNA synthesis of the hepatocytes and/or Kupffer cells in primary culture were analyzed. The ratio of liver weight to body weight and the labeling index in HPx rat were found to be significantly lower than those values in Hx rats. There were no significant differences in plasma alanine aminotransferase levels between the two groups. The inhibitory effect on DNA synthesis was observed with coculture of hepatocytes and Kupffer cells when the portal plasma obtained 1 hour after operation was added. We further observed that the conditioned medium of Kupffer cells stimulated by the addition of the portal plasma that was obtained 1 hour after HPx inhibited DNA synthesis of hepatocytes. This effect was abolished after incubation at 56 degrees C for 30 minutes. These results strongly suggest the existence of a growth inhibitory factor in portal plasma after HPx. This heat-labile growth inhibitory factor was released from Kupffer cells and would appear to act on hepatocytes in a paracrine manner.

Animals↗
PubMedDate not supplied

Chemical oxidation of nitrated polycyclic aromatic hydrocarbons: hydroxylation with superoxide anion radical.

Nitrated polycyclic aromatic hydrocarbon (nitroPAH) is a potent mutagen which is reductively and/or oxidatively metabolized. Biological oxidation of nitroPAH, such as hydroxylation and epoxidation, is known, but chemical oxidation has been reported in only a few papers. NitroPAH is barely oxidized by various chemical oxidants because of the electron deficient property of the aromatic ring with the nitro substituent. Nucleophilic reactivity of superoxide anion radical is known, and thus the oxidation of nitroPAH with the chemically generated superoxide anion radical was carried out in this study. When 1-nitropyrene was reacted with KO2/18-crown-6 in dimethylformamide, 5-, 6-, 8-, and 9-hydroxy-1-nitropyrenes and 1-hydroxypyrene were obtained in preparative yields. Three isomeric dinitropyrenes, 3-nitrofluoranthene, 6-nitrobenzo[a]pyrene, and 6-nitrochrysene, were oxidized to hydroxy derivatives, some of which correspond to the oxidative metabolite of nitroPAH. The oxidation of dinitropyrenes with trifluoroperacetic acid gave K-region oxidized products.

Free Radicals↗
PubMedDate not supplied

Di- and trinitrophenanthrenes: synthesis, separation, and reduction property.

Although nitrated polycyclic aromatic hydrocarbons (nitrated PAHs), specifically, dinitrated PAHs, have been indicated as potent mutagenic and carcinogenic environmental pollutants, only a few di- and trinitrophenanthrenes (DNPHs and TNPHs) have been reported up to the present time. Methods for the preparation of DNPHs and TNPHs by direct nitration of phenanthrene were established in this study. The reaction of phenanthrene with fuming nitric acid in acetic anhydride gave a complex mixture of DNPHs. Eleven DNPHs were isolated by using preparative HPLC with a total of 62.6% yield. Their chemical structures were determined using 1H NMR and electron impact mass spectrometry (EI-MS). The isolated DNPHs and their yields were 2,10-DNPH (14.2%), 1,10-DNPH (8.0%), 3,10-DNPH (6.9%), 3,6-DNPH (6.6%), 2,9-DNPH (5.3%), 1,6-DNPH (5.1%), 3,5-DNPH (4.6%), 4,9-DNPH (3.2%), 4,10-DNPH (3.1%), 1,5-DNPH (2.8%), and 2,6-DNPH (2.8%). Similarly, nine TNPHs were obtained from the nitrated reaction mixture of phenanthrene with fuming nitric acid without solvent: 3,6,9-TNPH (9.2%), 2,6,9-TNPH (9.0%), 1,6,9-TNPH (8.2%), 1,5,10-TNPH (9.0%), 2,6,9-TNPH (9.0%), 1,6,9-TNPH (4.0%), 1,7,9-TNPH (3.4%), 2,5,10-TNPH (2.5%), 2,6,10-TNPH (2.4%), 3,5,10-TNPH (1.8%), and 2,7,9-TNPH (0.2%) in 46.5% of the total yield. The reduction properties of the DNPHs and TNPHs were examined using cyclic voltammetry. The LUMO energy levels of the DNPHs and TNPHs calculated by the AM1 method were correlated to the first reduction potentials (E1/2). The coplanar or noncoplanar conformations of the nitro substituents to the phenanthrene ring system were also discussed.

Molecular Conformation↗
PubMedDate not supplied

Increased cyclooxygenase-2 expression is correlated with suppressed antitumor immunity in cervical adenocarcinomas.

Cyclooxygenase-2 (COX-2) inhibition suppressed the growth of various tumors. The augmentation of antitumor immunity by increasing cytotoxic lymphocytes may be an important mechanism for COX-2 inhibition. Among cervical cancers, adenocarcinomas present more aggressive behavior and overexpressed COX-2. The expression of COX-2 and the CD8+ lymphocyte infiltrations were evaluated in this study by immunohistochemistry. We studied COX-2 expression and CD8+ lymphocyte infiltration in 55 women with cervical adenocarcinomas. COX-2 expression and tumor stromal CD8+ lymphocytes were evaluated by semiquantified methods. Tumor intraepithelial lymphocytes were counted under microscopic field of x200. Correlations between these data and other clinicopathologic features were investigated. Thirty-seven out of 55 (67.3%) cervical adenocarcinomas significantly expressed COX-2. Patients who died within 5 years showed higher percentage of COX-2 expression than survivors (100% vs 58.1%, P < 0.05). Victims also showed lesser intraepithelial CD8+ lymphocyte counts than survived patients (3.4 vs 26.4, P < 0.05). COX-2 expression and tumor intraepithelial lymphocyte count were reversely correlated with each other (correlation index: -0.38, P < 0.01). Up-regulated COX-2 expression and lesser tumor intraepithelial CD8+ lymphocyte count are poor prognostic indicators for cervical adenocarcinoma patients. COX-2 may play an important role in the suppression of host antitumor immunity in cervical adenocarcinomas.

Adenocarcinoma↗
PubMedDate not supplied

Correlation between plasma and hepatic phosphatidylcholine hydroperoxide, energy charge, and total glutathione content in ischemia reperfusion injury of rat liver.

BACKGROUND/AIMS: Oxygen-derived free radicals are believed to be responsible for the hepatocellular injury leading to liver failure following ischemia-reperfusion in liver, endotoxemia and many other life-threatening illnesses. This study was designed to investigate the reactive oxygen species interaction in lipid peroxidation, the adenosine and energy charge levels of liver cells, and total glutathione content in ischemic-reperfusion injury of liver in rat. METHODOLOGY: To prevent intestinal congestion during the clamping of vascular structures, subcutaneous transposition of the spleen was done beforehand. Four to six weeks later, after the development of natural portal-systemic shunts, occlusion of the portal vein, hepatic artery and bile duct was performed for different periods; blood and liver samples were taken at different intervals after the release. On the basis of the ischemia-reperfusion time, the rats were divided into the following 9 groups: 30/0, 30/30, 30/60, 60/0, 60/30, 60/60, 90/0, 90/30, and 90/60. The following parameters were measured: total hepatic glutathione content, adenosine values (ATP, ADP, AMP), energy charge, phosphatidylcholine hydroperoxide (PCOOH) concentrations in liver and plasma, and serum transaminases (AST, ALT). Decreased liver glutathione stores (an indicator of increased oxidative stress), increased serum hepatic transaminases (an indicator of hepatocellular injury), and increased PCOOH (an indicator of cellular-membrane lipid peroxidation) were noted. RESULTS: The ATP level and energy charge diminished significantly with the increase in duration of ischemia and reperfusion. A close correlation between the PCOOH levels in plasma and liver was observed. Extreme damage was noted in the 90-minute ischemia with 60-minute reperfusion group. The hepatic total glutathione level was reduced to the lowest level in the 90/60 group and it correlated with the energy charge level, denoting the highest degree of oxidative stress sustained by the liver cells in this group. CONCLUSIONS: These results indicated that prolonged hepatic ischemia with reperfusion produced bursts of oxygen-derived free radicals which overwhelmed the defense mechanisms of the cells, with a resultant decrease in energy charge associated with an increase in membrane lipid peroxidation. These findings not only provide confirmation of previously reported hepatocellular injury by free radicals generated after reperfusion, but they also establish the use of PCOOH analysis in liver and plasma as a sensitive and specific indicator of the injury process in time. The plasma PCOOH level may be a useful indicator of free radical induced hepatic membrane lipid peroxidation during ischemia-reperfusion, and might be employed in clinical studies of the therapeutic effects of drugs in various liver diseases, as well as for determining the prognosis after different kinds of hepatic operations.

Adenine Nucleotides↗
PubMedDate not supplied

Reconstructive procedure after distal gastrectomy to prevent remnant gastritis.

BACKGROUND/AIMS: Gastroduodenostomy (Billroth I) or gastrojejunostomy (Billroth II) after distal gastrectomy is associated with duodenogastric reflux and remnant gastritis. This study sought to determine which reconstructive procedure is least likely to cause remnant gastritis and to determine the correlation between duodenogastric reflux and remnant gastritis. METHODOLOGY: Sixty patients who underwent curative distal gastrectomy for gastric cancer were classified into three groups by reconstructive procedure: group A, Roux-Y (n=18); group B, Billroth I (n=25); group C, Billroth II (n=17). Intragastric bile reflux was monitored using the Bilitec 2000 14 days after surgery, and endoscopy was performed and a patient questionnaire was completed 12 weeks after surgery. RESULTS: Bile reflux occurred in 23.9%, 40.4%, and 73.4% of the time (p<0.001), and remnant gastritis developed in 33%, 76%, and 100% of patients (p<0.001), in groups A, B, and C, respectively. Helicobacter pylori infection did not correlate with remnant gastritis (p=0.57). Symptoms following Roux-Y reconstruction were comparable to those following Billroth I and II reconstructions. CONCLUSIONS: Roux-Y reconstruction following distal gastrectomy is superior to Billroth I and II reconstruction in preventing remnant gastritis because it reduces duodenogastric reflux.

Aged↗