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N Uehara

Publications and source records attributed to N Uehara.

At least 73 records · Page 4Linked to original sources
PubMed1987

[Antitumor activity of new derivatives of camptothecin].

With the purpose of obtaining more potent and less toxic camptothecin (CPT) analogs, we prepared many derivatives of CPT. Among them, 7-ethyl-CPT (SN 22) and 7-ethyl-10-hydroxy-CPT (SN 38) showed strong antitumor activity with less toxicity. They were, however, insoluble and when they were made soluble, their activity was markedly diminished, as a result of cleavage of the delta-lactone ring. We therefore attempted to make soluble derivatives without breaking the delta-lactone ring and obtained 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-CPT (CPT-11), which showed very strong antitumor activity by i.p., i.v. or p.o. administration against the ascites type of L1210 leukemia, P388 leukemia, sarcoma 180, Meth A fibrosarcoma, B16 melanoma, Ehrlich carcinoma and MH134 hepatoma and the solid type of sarcoma 180, Meth A fibrosarcoma, Lewis lung carcinoma, C3H/HeN mammary carcinoma, Ehrlich carcinoma and MH134 hepatoma. The antileukemic activity of CPT-11 against L1210 was much higher than that of adriamycin. The acute toxicity of CPT-11 was extremely low, particularly in the case of oral administration, the LD50 being 765.3 mg/kg, 22 times greater than that of CPT-Na.

Animals↗
PubMed1985

Antitumor polysaccharides from P. ostreatus (Fr.) Quél.: isolation and structure of a beta-glucan.

We isolated an antitumor glucan (HA beta-glucan) from the neutral polysaccharide fraction (A3) of a hot-water extract of the edible mushroom P. ostreatus (Fr.) Quél. Purification was accomplished by extractions with 20% sodium chloride solution saturated with thymol and by precipitations with ethanol from dimethyl sulfoxide solution. The glucan showed marked antitumor activity at a dose of 0.1 mg/kg. It is a highly branched (1----3)-beta-glucan having an average structure represented by a pentasaccharide segment consisting of one nonreducing terminal, one 3,6-di-O-substituted, and three 3-mono-O-substituted beta-D-glucopyranosyl residues. This structure was confirmed by examining 13C-n.m.r. spectra taken at 75.46 MHz.

Animals↗
PubMed1985

Biopharmaceutical evaluation of methylcellulose as an excipient for nitroglycerin tablets.

To examine the bioavailability of nitroglycerin in sublingual tablet, 5 healthy adult volunteers underwent simultaneous sublingual administration of a tablet prepared with methylcellulose and a tablet prepared with lactose containing 0.15 mg of nitroglycerin and 0.15 mg of nitroglycerin-15N3, respectively. In 4 of 5 volunteers, no difference in plasma concentration determined by gas chromatography-mass spectrometry (GC-MS) was observed between 2 tablets described above, so it was well accepted that nitroglycerin in tablets prepared with methylcellulose had a similar bioavailability to that in tablets prepared with lactose. The simultaneous administration of the 2 nitroglycerin tablets to a healthy volunteer, one of which containing the drug labeled with a stable isotope followed by GC-MS assay, seems to be the most suitable method for a precise comparison of bioavailability of the formulations.

Adult↗
PubMed1985

The therapeutic effects of orally administered 5'-deoxy-5-fluorouridine, 1-(2-tetrahydrofuryl)-5-fluorouracil and 5-fluorouracil on experimental murine tumors.

The antitumor effects of three 5-fluorouracil-related compounds, 5'-deoxy-5-fluorouridine (5'-DFUR), 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) and 5-fluorouracil (5-FU) itself, on several experimental murine tumors were compared after oral administration. 5'-DFUR showed strong antitumor activity against the solid type of four kinds of tumors tested with a wide range of effective doses, and also showed moderate antitumor activity against three kinds of solid tumors with a narrow range of effective doses. 5'-DFUR was effective against a few kinds of ascites tumors. In general, the antitumor activity of FT-207 was not very strong, with narrow ranges of effective doses under the present conditions. 5-FU showed strong toxicity but at lower doses its antitumor effectiveness was almost the same as that of FT-207. When the doses were divided into three and the divided dose was given orally three times a day for five consecutive days to mice bearing L1210 leukemia, this modality (with any of the three drugs) enhanced the ILS of the mice by two to three times in the case of the ascites type but not the solid type of L1210. The chemotherapeutic index in oral treatment of the solid type of tumors was higher for 5'-DFUR than for FT-207 or 5-FU. The minimum lethal doses in oral administration for five consecutive days were about 3, 1.5 and 0.5 mmol/kg/day for 5'-DFUR, FT-207 and 5-FU, respectively. In conclusion, 5'-DFUR appeared to have stronger antitumor activity and less toxicity than FT-207 and 5-FU, and it is therefore expected to be clinically useful.

Animals↗
PubMed1983

Characteristics of the uptake of cysteine-containing leukotrienes by isolated hepatocytes.

Leukotrienes were transported into rat hepatocytes by a temperature- and energy-dependent mechanism. The uptake was saturable with high- and low-affinity sites (Km values approx. 1 and 17 microM). Competition and kinetic experiments indicated that leukotrienes C4, D4 and E4 were transported by a common mechanism. The maximal velocity of transport was about 50% higher for leukotrienes D4 and E4 than for leukotriene C4. Leukotriene B4, glutathione disulfide, and the glutathione-S-conjugate of acetaminophen did not interfere with the transport of leukotriene C into hepatocytes. This suggests that the process is specific for cysteine-containing leukotrienes. It is likely that the transport mechanism described here participates in biliary excretion of leukotrienes. This route was previously found to be a major one for elimination of leukotriene C3 in mice and guinea-pigs.

Acetaminophen↗
PubMed1983

Pharmacokinetics and metabolism of sodium 2-mercaptoethanesulfonate in the rat.

The synthetic low-molecular-weight thiol, 2-mercaptoethanesulfonate (mesna), exerts efficient protection against oxazaphosphorine-induced urothelial toxicity by binding the renally excreted and concentrated toxic metabolite(s). In this study, the pharmacokinetics and metabolism of mesna and its disulfide form (dimesna) have been investigated in the intact rat and in several in vitro systems, including isolated perfused organs, freshly isolated cells, and subcellular fractions; the mechanism of reduction of dimesna to form the pharmacologically active thiol mesna has been further studied with purified enzyme preparations. The results may be summarized as follows: (a) After p.o. administration, mesna and dimesna are both absorbed from the intestine, and dimesna undergoes reduction to mesna during intestinal absorption; (b) when present in plasma, mesna is rapidly oxidized to dimesna by a metal-dependent reaction; (c) mesna and dimesna pass unchanged through the hepatic vasculature, are not taken up into liver cells, and are not excreted in bile; (d) in the kidney, dimesna is filtered through the glomeruli and subsequently reabsorbed, whereupon reduction to the pharmacologically active thiol form occurs in the renal tubular epithelium, and the thiol is then reexcreted into the tubular lumen; (e) reduction of dimesna to mesna occurs in intestinal and renal epithelial cells by a mechanism involving the cytosolic enzymes thiol transferase and glutathione reductase. Thus, the formation of the pharmacologically active thiol form from dimesna is associated with the consumption of equimolar concentrations of reduced glutathione.

Animals↗
PubMed1982

Renal transport and disposition of Na-2-mercaptoethane sulfonate disulfide (dimesna) in the rat.

The transport and reduction of dimesna (Na-2-mercaptoethane sulfonate disulfide) was studied in vitro using isolated, perfused rat kidney, and isolated renal epithelial cells. Cellular uptake of dimesna was found to be dependent on an active transport mechanism working across the luminal brush border, with an app. Km of approximately 22 microM and Vmax approximately 1.4 nmol . 10(6) cells-1 . min-1. Among other low molecular thiols or disulfides reduced glutathione was the only one to exert competitive inhibition. gamma-GT-activity or cellular GSH status had no influence on renal uptake of dimesna, but the intracellular reduction rate was dependent on access to reduced glutathione as a cofactor.

Animals↗