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Biomedical subjects

S Fukushima

Publications and source records attributed to S Fukushima.

At least 361 records · Page 20Linked to original sources
PubMed1989

Hydrolysis of 3',5'-dioctanoyl-5-fluoro-2'-deoxyuridine (FdUrd-C8) in rabbit and human plasma and its release from oily solution.

Hydrolysis of 3',5'-dioctanoyl-5-fluoro-2'-deoxyuridine (FdUrd-C8), a lipophilic prodrug of 5-fluoro-2'-deoxyuridine (FdUrd), 3'-octanoyl-5-fluoro-2'-deoxyuridine(3'-octanoyl FdUrd) and 5'-octanoyl-5-fluoro-2'-deoxyuridine (5'-octanoyl FdUrd) in the rabbit and human plasma and release of FdUrd-C8 and its hydrolyzed species from Lipiodol Ultra-Fluid (Lipiodol), an oily lymphographic agent, containing FdUrd-C8 were examined. The rates of hydrolysis of FdUrd-C8, 3'-octanoyl FdUrd and 5'-octanoyl FdUrd in the rabbit plasma were fast and almost the same among the three compounds; half lives were 2.4, 3.6 and 3.9 min for 5'-octanoyl FdUrd, FdUrd-C8 and 3'-octanoyl FdUrd, respectively. In the human plasma, however, the rates of hydrolysis were much different among the three compounds and were slower than those in the rabbit plasma; half lives were 11.5, 130 and 1020 min for 5'-octanoyl FdUrd, FdUrd-C8 and 3'-octanoyl FdUrd, respectively. Ratios of the rate constant of 5'-octanoyl FdUrd to that of 3'-octanoyl FdUrd were 1.6 and 85.7 in the rabbit plasma and in the human plasma, respectively. In a release study, although detected species in a release medium were different between the rabbit plasma and the human plasma and the amount of each species reflected the characteristics of esterase in each plasma, the total amounts of compounds released were almost the same both in the rabbit plasma and the human plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Enzymatic and chemical stability of 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides: potential anti-acquired immunodeficiency syndrome agents.

The enzymatic and chemical stability of three 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides has been studied. Chemical degradtion of the analogues was measured in the pH range of 1.0-9.0. 2',3'-Dideoxy-2',3'-didehydrocytidine (DDCN) degraded rapidly under acidic conditions, but the chemical stability was greater under basic conditions. The chemical degradation of 2',3'-dideoxy-2',3'-didehydrouridine (DDUN) and 2',3'-dideoxy-2',3'-didehydrothymidine (DDTN) was not pH dependent and was faster than that of cytarabine. Enzymatic degradation of DDCN, DDUN and DDTN was not observed in human plasma, though cytarabine was degraded enzymatically under the same conditions. DDCN was also not degraded in the presence of mouse kidney cytidine deaminase.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Studies on 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides. II. N4-benzoyl-2',3'-dideoxy-2',3'-didehydrocytidine as a prodrug of 2',3'-dideoxy-2',3'-didehydrocytidine (DDCN).

N4-Benzoyl-2',3'-dideoxy-2',3'-didehydrocytidine (Bz-DDCN) was synthesized as a novel prodrug of 2',3'-dideoxy-2',3'-didehydrocytidine (DDCN), which is a reverse transcriptase inhibitor and is considered to be a potential anti-acquired immunodeficiency syndrome agent. Chemical and enzymatic regeneration of DDCN from the prodrug has been investigated in both in vitro and in vivo experiments. Bz-DDCN regenerated DDCN under basic conditions (greater than pH 8), while cleavage of the N-glycosidic linkage and production of N4-benzoylcytosine were observed under acidic conditions (less than pH 6). DDCN was enzymatically regenerated from the prodrug in the presence of several enzyme preparations, including human plasma. DDCN and Bz-DDCN were intravenously administered to mice and the plasma concentrations of DDCN and the prodrug were measured. Though DDCN levels following direct DDCN administration decreased exponentially with a half-life of 14.5 min, the plasma levels of DDCN following the prodrug administration were sustained above 2 microM for over 3 h.

Animals↗
PubMed1989

[Studies on stroke-prone spontaneously hypertensive rats (SHRSP) fed a high-fat and high-cholesterol diet--changes in serum concentrations and distributions of apolipoproteins A-I, A-IV and E].

The effects of a high-fat and high-cholesterol diet (HFC diet) on serum lipoproteins and apolipoproteins were studied in stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Kyo: Wistar rats (WKY). In particular, the changes in serum concentrations and distributions among lipoprotein fractions of apolipoproteins A-I, A-IV and E (apo A-I, A-IV and E) were investigated in detail. These apolipoproteins are the main protein constituents of high density lipoprotein (HDL) which is considered to be an anti-atherogenic factor and accounts for a large part of the serum lipoproteins in the rat. Serum lipoprotein fractions were isolated by stepwise density-gradient ultracentrifugation. The alterations in lipoprotein fractions and apolipoproteins in lipoprotein fractions were roughly estimated by native gradient polyacrylamide gel electrophoresis and sodium dodecyl sulfate (SDS)-gradient polyacrylamide gel electrophoresis. Next, the concentrations of apo A-I, A-IV and E in serum, serum lipoprotein fractions and serum lipoprotein-free fraction were measured by rocket immunoelectrophoresis according to the method of Laurell as modified by us. Cholesterol was enzymatically determined by a commercially available kit. The results obtained were as follows: 1) A remarkable increase in the very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) fractions was observed in WKY and SHRSP. This was associated with a remarkable increase in the cholesterol and apo B contents and with a significant increase in the apo E content. These changes in the VLDL and IDL fractions were more drastic in SHRSP than in WKY, which suggests the promotive effect of hypertension in SHRSP on the production of VLDL and IDL fractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

[Studies on stroke-prone spontaneously hypertensive rats (SHRSP) fed a high-fat and high-cholesterol diet--effect of taurine on serum lipoprotein metabolism in hypercholesterolemic rats].

It is well known that taurine, a final metabolite of sulfur-containing amino acids, plays an important role in bile acid metabolism and that it also has a moderately hypotensive effect. Moreover, it has recently been revealed that taurine shows a hypocholesterolemic effect in animals with experimentally induced hypercholesterolemia. However, the hypocholesterolemic mechanism remains unresolved. Stroke-prone spontaneously hypertensive rats (SHRSP) easily develop hypercholesterolemia when fed a high-fat and high-cholesterol diet (HFC diet). In our previous paper, we reported changes in the concentrations and distributions of serum lipoproteins and apolipoproteins in hypercholesterolemic SHRSP and Kyo: Wistar rats (WKY) induced by HFC feeding. In this paper, to elucidate the mechanism of the hypocholesterolemic effect of taurine, we investigated the effects of taurine on concentrations and distributions of serum lipoproteins and apolipoproteins in hypercholesterolemic SHRSP and WKY induced by HFC feeding. The results obtained were as follows: 1) The hypocholesterolemic effect of taurine in hypercholesterolemic SHRSP was remarkable in comparison with that in hypercholesterolemic WKY. 2) The hypocholesterolemic effect of taurine was mainly due to a marked suppression of extreme elevations of cholesterol contents in the VLDL and IDL fractions of both strains. This was associated with a decrease in the elevated contents of apo B and apo E which are major components of VLDL and IDL. This suppressive effect was more obvious in SHRSP than in WKY, which explains the greater hypocholesterolemic effect of taurine in SHRSP. It could be that, as a result of taurine administration, the catabolism of cholesterol to bile acid in the liver is accelerated, followed by a decrease of the hepatic cholesterol pool, resulting in a suppression of the synthesis and/or secretion of VLDL (beta-VLDL) in the liver. 3) The hypocholesterolemic effect of taurine was also observed in the LDL fractions of both strains, but the effect was not as strong as that observed in the VLDL and IDL fractions. This effect might be attributable to suppression of the synthesis and/or secretion of LDL in the liver and a decrease in the elevated content of apo E HDL (HDLc) which spans two density fractions (the LDL and HDL fractions). 4) In HDL fractions of both strains, the decreased content of apo E HDL (HDL1 and HDLc) was even lower, whereas the decreased apo A-I content in the HDL fraction of SHRSP was significantly restored and the cholesterol level was slightly elevated.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

[Studies on stroke-prone spontaneously hypertensive rats (SHRSP) fed a high-fat and high-cholesterol diet--effects of salt intake on serum lipoprotein and apolipoprotein metabolism].

Recently, food intake in Japan has been characterized by an increase in fat intake, especially animal-fat intake and the maintenance of excess salt (sodium chloride) intake. It is generally accepted that the increase in fat intake is closely related to atherosclerosis, and excess salt intake is a high risk factor for the development of hypertension and cerebrovascular lesions. So far, in almost all reports, the increase in fat intake and excess salt intake have been studied independently, and there have been few reports on the combined effects of these two factors. Taking the above things into consideration, it would seem to be very interesting to investigate the effect of excess salt intake on lipid metabolism. In this paper, we studied the effects of excess salt intake on lipoprotein and apolipoprotein metabolisms, using stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Kyo: Wistar rats (WKY) as model animals. The results obtained were as follows: A significant increase in the concentration of serum total cholesterol (TC) was observed in SHRSP and WKY, when the rats were given a regular diet (CE-2, Clea Japan Inc.) and 1% sodium chloride solution (1% NaCl) as drinking water for 4 weeks. This was accompanied by a tendency toward increases in the concentrations of serum apolipoproteins in both strains. These results suggest that excess salt intake could accelerate the production of serum total lipoproteins in SHRSP and WKY, when the rats are fed a regular diet. Next, 1% NaCl and a high-fat and high-cholesterol diet (HFC diet) were simultaneously given to SHRSP and WKY for 6 weeks. The effects of simultaneous administration on lipoprotein and apolipoprotein metabolisms were compared with those of HFC feeding. One percent NaCl did not markedly affect hypercholesterolemia in WKY, while it induced more marked hypercholesterolemia in SHRSP that was associated with extreme elevations of serum TC and the atherogenic index (A.I.). This deleterious effect of 1% NaCl in SHRSP was due to drastic elevations of cholesterol contents in the very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) fractions. This was also associated with marked increases in apo B contents in the VLDL, IDL and LDL fractions and significant increases in apo E contents in the VLDL and IDL fractions. These results indicate that 1% NaCl induced much larger increases in serum atherogenic beta-lipoproteins in SHRSP.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

[Modifying effects of beraprost sodium (TRK-100) on N-methyl-N-nitrosourea (MNU) carcinogenesis in F344 rats].

The potential tumor-promoting effects of beraprost sodium (TRK-100), stable analogue of prostacyclin (PGI2), were investigated in rats pretreated with N-methyl-N-nitrosourea (MNU) which is a potent initiator of tumor development in a variety of organ or tissues. Male F344 rats were initially given injections of MNU (20 mg/kg b.w. i.p.) twice a week for 3 weeks, and then administered drinking water containing 6, 2, 0.7 or 0.2 ppm of beraprost sodium for the next 29 weeks. For comparison, positive control groups received N-propyl-N-nitrosourea (PNU), which is a carcinogen in hematopoietic system and small intestine on F344 rat, at the dose of 200, 50 and 12.5 ppm in their drinking water. Appropriate non-treated controls were also included. Numerous tumors were observed in many organs including the hematopoietic system, digestive tract, nervous system, Zymbal's gland (auditory sebaceous glands) and peritoneal mesothelium. However, no tumor-enhancing effects of beraprost sodium were observed. In contrast, the groups treated with PNU demonstrated increased development of tumors in the tongue, forestomach, large intestine and Zymbal's gland. These results thus indicate that beraprost sodium is not capable of modulating the development of MNU-induced tumors.

Animals↗
PubMed1989

[Intra-arterial injection of cisplatin suspension in Lipiodol (LPS) in the treatment of hepatocellular carcinoma].

Cisplatin suspension in Lipiodol (LPS) was prepared for the treatment of hepatocellular carcinoma by intra-hepatic arterial injection. In a rabbit liver cancer model, concentrations of cisplatin in tumor were more than 20 times higher than those in a nontumorous part of the liver at 5 min after LPS injection into the hepatic artery. Cisplatin at high concentrations was detected at 7 days after injection. The concentrations in other organs were lower except in the gall-bladder. In clinical trials for 71 patients with hepatocellular carcinoma, partial response was observed in 33 cases (46.5%) and minor response in 20 cases (28.2%). The survival rate was 77% at 6 month and 55% at one year. Although fever, nausea, vomiting and epigastralgia were observed as side effects, these were temporary. Acute gastroduodenal mucosal lesions, cholecystitis, pancreatitis, delayed jaundice and hepatic encephalopathy were observed as complications and super selective cannulation was necessary for their prevention.

Animals↗
PubMed1989

Synthesis and angiotension converting enzyme inhibitory activity of L-lysyl-N-substituted glycine derivatives.

The synthesis and biological activity of novel L-lysyl-N-substituted glycine derivatives which exhibit in vitro and in vivo angiotensin converting enzyme (ACE) inhibition, are described. Particularly, N-[N alpha-(1-carboxy-3-phenylpropyl)-L-lysyl]-N-(4-phenylcyclohexyl)glycine (11e), N-[N alpha-(1-carboxy-3-cyclopentylpropyl)-N epsilon-carbobenzoxy-L- lysyl]-N-cyclopentyl glycine (9h) and N-[N alpha-[1(S)-carboxy-3-cyclohexylpropyl]-L-lysyl]-N-cyclopentyl glycine (19a) showed a strong inhibitory activity at IC50 as low as 0.65, 0.64 and 0.11 nmol/l, respectively. The most potent activity in vivo was observed with the compound 19a after i.v. administration in the rat.

Angiotensin I↗
PubMed1989

[Phase II study of 5-FU tablet in bladder tumor].

A cooperative-phase II study of 5-FU tablet at a dose of 200 to 300 mg/day (b.i.d. or t.i.d) on 27 patients with bladder cancer was performed at Yokohama City University and other affiliated hospitals. The therapeutic responses were evaluated by Koyama-Saito's criteria in 24 out of 27 patients, and 3 PR, 2 MR, 16 NC and 3 PD were obtained. The overall response rate was 12.5% (3/24). All of the responders received 5-FU tablets at a daily dose of 300 mg. Side effects were found in 2 out of 26 patients (7.7%). These were slight gastrointestinal symptoms. These results suggest that 5-FU tablet is a useful drug for bladder cancer.

Administration, Oral↗
PubMed1989

[A case of hemangiopericytoma in the retroperitoneal cavity and a review of literature in Japan].

A case of hemangiopericytoma in the pelvic retroperitoneum is reported. The patient, a 45-year-old man, visited us with a complaint of sudden urinary retention. Intravenous pyelogram and computerized tomographic scan revealed a large pelvic mass displacing the bladder to the left superiorly. Laparotomy was performed, and biopsy showed the mass to be a malignant hemangiopericytoma. He underwent a surgical excision after receiving irradiation to the true pelvis and embolization of right internal iliac. He developed multiple pulmonary and liver metastases and died 2 years after surgery. Thirty cases of retroperitoneal hemangiopericytoma reported in Japan are reviewed.

Hemangiopericytoma↗
PubMed1989

[Basic studies on optimal intra-arterial infusion rate of cisplatin].

The relationship between platinum concentration in tissues, free CDDP concentration in plasma and infusion rate was investigated in order to determine the optimal intra-arterial infusion rate of CDDP for chemotherapy of cervical carcinoma. Platinum concentrations in uterus were in the same level in the intravenous infusion groups independent of the infusion rate. In the intra-arterial infusion groups, platinum concentrations in the uterus increased as the infusion rate decreased from 24 to 0.8 mg/hr, although Cmax and AUC were decreased. Platinum concentrations in the ovary supplied by another artery were not influenced by the intra-arterial infusion rate. It is suggested that uptake of CDDP in the targeted tissues can be increased by control of intra-arterial infusion rate.

Animals↗
PubMed1988

Modifying effects of concomitant treatment with butylated hydroxyanisole or butylated hydroxytoluene on N,N-dibutylnitrosamine-induced liver, forestomach and urinary bladder carcinogenesis in F344 male rats.

The modifying effects of concomitant antioxidant treatment on N,N-dibutylnitrosamine (DBN)-induced carcinogenesis were investigated. Male F344 rats were given 0.05% DBN in their drinking water for 16 weeks, and simultaneously administered powder diet containing 2.0% butylated hydroxyanisole (BHA) or 0.7% butylated hydroxytoluene (BHT) for 16 weeks. Control animals received drinking water containing 0.05% DBN without antioxidant treatment. The final incidences of hepatocellular carcinomas were 100, 100 and 40% in the DBN plus BHA, DBN plus BHT and DBN treated groups, respectively, the difference being significant (P less than 0.001). Lung metastases were only observed in the DBN plus BHT group and DBN plus BHA group (50%, P less than 0.001; 7%, respectively). The incidence of papillary or nodular hyperplasia of the urinary bladder in the DBN plus BHA group was significantly higher than that of the control (P less than 0.05). Furthermore, esophageal carcinomas and papillomas were observed in all DBN treated groups, with no inter-group significant variation in yield. On the other hand, combination of DBN treatment with BHA or BHT significantly reduced the resultant incidences of forestomach hyperplasia. The results clearly demonstrated that concomitant administration of antioxidants, and in particular BHT, can modify DBN carcinogenesis.

Animals↗
PubMed1988

L-ascorbic acid amplification of second-stage bladder carcinogenesis promotion by NaHCO3.

The dose dependence of NaHCO3 promotion of urinary bladder carcinogenesis and the effects of additional L-ascorbic acid (AsA) administration were investigated subsequent to initiation. Male F344 rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in their drinking water for 4 weeks and then, starting 3 days after cessation of carcinogen treatment, received basal diet containing NaHCO3 at levels of 0, 0.375, 0.75, 1.5, and 3.0% with or without a 5% AsA supplement for 32 weeks. NaHCO3 dose-dependently increased the incidence and numbers of urinary bladder carcinomas in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine. 5% AsA, while itself exerting no promoting effect, amplified the enhancing influence of NaHCO3 on induction of urinary bladder carcinomas. The same dose-dependent elevation of urinary pH and Na+ concentration was associated with NaHCO3 treatment with or without AsA. NaHCO3 significantly increased DNA synthesis in the urinary bladder epithelium and the additional treatment with AsA was associated with a significant further elevation. Thus, increased urinary pH and Na+ concentrations appear to play important roles in NaHCO3 promotion and AsA amplified this promotion. NaHCO3 treatment, with or without AsA, induced cellular proliferation, although it is unclear whether this is an essential factor.

Animals↗
PubMed1988

Modification of N-methyl-N'-nitro-N-nitrosoguanidine-induced forestomach and glandular stomach carcinogenesis by phenolic antioxidants in rats.

The modifying effects of five phenolic antioxidants on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-initiated forestomach and glandular stomach carcinogenesis were investigated in male F344 rats. Groups of 20 rats were given an intragastric dose of 150 mg/kg body weight MNNG, and starting from 1 week later received diet supplemented with 0.8% catechol (CC), 1.0% 2-tert-butyl-4-methylphenol, 1.5% p-tert-butyl-phenol, 1.5% methylhydroquinone, 1.5% 4-methoxyphenol (4MP), or basal diet alone for 51 weeks. Further groups of 10-15 rats were maintained as controls without prior treatment with MNNG. The incidences of squamous cell carcinoma of the forestomach in MNNG-treated animals were significantly elevated by the diets containing CC (P less than 0.001), 2-tert-butyl-4-methylphenol (P less than 0.001), or p-tert-butylphenol (P less than 0.01), while the development of carcinoma in situ was inhibited by 4MP (P less than 0.01). Treatment with CC, 2-tert-butyl-4-methylphenol, p-tert-butylphenol, or 4MP alone induced forestomach hyperplasia at incidences of 86.7, 40, 93.3, and 100%, respectively. In the pyloric region of the glandular stomach, the development of adenomatous hyperplasia and adenocarcinoma after MNNG treatment was significantly enhanced by diet containing CC (P less than 0.001). Moreover, treatment with CC alone induced 100% adenomatous hyperplasia and induced adenocarcinoma in 20% of animals. These results clearly demonstrated that while antioxidants causing proliferation in forestomach epithelium can markedly enhance carcinogenesis in this tissue, others displaying the same or greater potential for generating a hyperplastic response, like 4MP, can exert an inhibitory effect. In addition, it was shown that CC, which is widely present in our environment, is an unequivocal glandular stomach carcinogen also possessing strong enhancing activity for MNNG-induced lesion development.

Animals↗