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Biomedical subjects

M Hashida

Publications and source records attributed to M Hashida.

At least 145 records · Page 8Linked to original sources
PubMed1987

Enhanced gastrointestinal absorption of drugs in rats pretreated with the synthetic immunomodulator, levamisole.

The effect of levamisole on drug absorption from the rat small intestine has been investigated by means of an in-situ recirculation technique. The absorption of salicylic acid, sulphanilamide and aminopyrine was significantly increased by the intraperitoneal administration of levamisole (2 mg) 1 day before the absorption studies, but there was no significant effect on absorption from the small intestine of indomethacin, bromthymol blue, sulphafurazole (sulfisoxazole), quinine, sulphanilic acid, phenol red (phenolsulfonphthalein), L-tryptophan and fluorescein isothiocyanate-dextrans. The effect of levamisole on the absorption from the small intestine of salicylic acid was marginally dose- and time-dependent, the maximal effect being observed after pretreatment with 2 mg of levamisole 1 day before the absorption studies. Sulphanilamide, similarly, was better sorbed from the small intestine and also from the stomach in the presence of levamisole. The intraperitoneal administration of levamisole may influence the absorption of some low molecular weight drugs from the gastrointestinal tract.

Animals↗
PubMed1987

Effects of mitomycin C, 5-fluorouracil and cyclophosphamide on drug absorption, enzyme activities and mucosal lipid composition of intestine.

The effect of a single intravenous or oral administration of mitomycin C (MMC), 5-fluorouracil (5-FU) or cyclophosphamide (CP) on drug absorption was studied in rats in relation to changes in membrane characteristics. At 48 h after pretreatment, a differential effect on the absorption of sulfanilamide and L-tryptophan was observed in in situ recirculation experiments. Intravenous MMC administration suppressed the absorption of both sulfanilamide and L-tryptophan to a similar extent as a higher oral dose of this agent. Dosing with 5-FU via both routes caused the largest but almost equal suppression of L-tryptophan absorption. However, CP had no effect on the absorption of the two drugs. Differences in these effects were considered to reflect their pharmacological and pharmacokinetic properties. Absorption of drugs from the small intestine had a positive correlation with small intestinal wet weight regardless of the antitumor drug used, pretreatment doses and routes of administration and the results indicated that the change in absorptive surface area played a major role in this phenomenon. Toxicity to intestinal mucosa was shown to derive from an effect on dividing cells in the crypts because MMC and 5-FU preferentially decreased thymidine kinase activity. However, at the membrane level, increased mucosal membrane permeability was also confirmed by measuring the release rates of D-glucose from liposomes consisting of mucosal total lipids obtained from the antitumor drug-treated rats. Pretreatment with lipophilic and polymeric prodrugs of MMC did not exhibit any effect on drug absorption and thus, the possibility of alleviation of toxicity and adverse reactions via the prodrug approach was suggested.

Animals↗
PubMed1986

Changes in D-glucose uptake by brush-border vesicles from small intestine of rats treated with mitomycin C.

The effect of mitomycin C pre-administration on the D-glucose transport system in the intestinal brush-border membrane of rat small intestine was examined by a rapid filtration technique. Forty-eight hours following the intravenous administration of mitomycin C, there were extensive and severe mucosal derangements. At this time point, membrane vesicles were prepared from the mitomycin-C-pretreated and control rats. Binding studies indicated that D-glucose entered into the intravesicular space of vesicles even in the case of mitomycin-C-pretreated rats. Vesicles obtained from both the mitomycin-C-pretreated and the control rats showed sodium-dependent uptake of D-glucose, but the initial uptake at 15 sec was significantly greater in control rats than in mitomycin-C-pretreated rats. Comparison of kinetic parameters of D-glucose transport indicated that Km was not significantly different between control and mitomycin-C pretreated rats. The pretreatment with mitomycin C decreased Vmax and increased the diffusional permeability to D-glucose considerably. These changes induced by mitomycin C seemed to derive not from a direct effect on mature enterocytes but from an indirect effect secondary to mitotic inhibition in the crypts.

Animals↗
PubMed1986

Characterization of liposomes and an emulsion containing mitomycin C or lipophilic mitomycin C prodrugs.

The characteristics of liposomes and an oil-water emulsion containing either mitomycin C (MMC) or its lipophilic prodrugs were investigated. Prodrugs were incorporated into liposomes and oil droplets of an oil-water emulsion, and this incorporation was dependent on the lipid content of the liposomes and droplets. A good correlation was observed between the calculated lipid:water partition ratios and partition coefficients in chloroform:water. The prodrugs were rapidly distributed between the lipid and aqueous phases when they were injected into the dispersion medium of empty liposomes and an oil-water emulsion, or when the formulations incorporating prodrugs were diluted with water. Addition of prodrugs to liposomes containing perylene resulted in a decrease of fluorescence. Based on these findings, prodrugs were concluded to be incorporated into lipidic dispersion formulations based on their partitioning behavior. N1a-[(Nonyloxy)carbonyl]MMC (7) showed the highest incorporation into lipidic formulations, while prodrugs with moderate lipophilicities were rapidly released from lipid particles. Liposomes incorporating 7 maintained their multilamellar vesicular form as shown by electron microscopy and by examining their entrapping capacity for water soluble marker dyes. The release of prodrug 7 from both formulations was slow in a buffer solution, but considerable release and conversion to the parent drug were observed when rat plasma was added to the same system. These results suggest that the stability of MMC could be improved by incorporation into lipidic formulations and that a suitable release rate in vivo could be accomplished by use of a prodrug.

Chemical Phenomena↗
PubMed1986

Characterization of mitomycin C-induced gastrointestinal damage: changes in the gastric absorption of drugs in rats.

The effect of mitomycin C (MMC) pre-administration intravenously on the absorption of drugs from rat stomach has been examined by means of the in-situ loop technique. 48 h after the MMC-treatment, the absorption of salicylic acid, aspirin and sulphanilic acid was not influenced but that of sulphanilamide was significantly increased compared with the control. At 96 h, a differential effect of MMC on the absorption of each drug was seen: the absorption of weakly acidic drugs was significantly decreased while that of bases and strong sulphonic acid increased. The decreased absorption of salicylic acid and aspirin correlated with the reduced gastric mucosal blood flow. At 96 h there were severe haemorrhagic lesions in the gastric mucosae. The increase in absorption of poorly absorbed drugs could be ascribed to the increased permeability of the blood-gastric epithelium barrier as was evidenced by leakage of Evans Blue.

Animals↗
PubMed1986

Immunological control of drug absorption from the gastrointestinal tract: the mechanism whereby intestinal anaphylaxis interferes with the intestinal absorption of bromthymol blue in the rat.

Rats were immunized intraperitoneally with ovalbumin and the disappearance of bromthymol blue (BTB) from the intestinal lumen, its accumulation in the tissue, and its net absorption were examined by means of an in-situ recirculation technique during local anaphylaxis. The disappearance of BTB from the intestinal lumen and its net absorption were significantly reduced, but there was no significant effect on its accumulation in the tissue. The pH value of the luminal solution and the perfusate volume were not influenced by intraluminal challenge with the antigen in ovalbumin-immunized rats. In addition, no significant effect was observed on intestinal permeability to BTB in the in-vitro everted sac technique. The intestinal blood flow, measured by a hydrogen clearance method, was not reduced significantly by the intraluminal exposure to antigen. There was enhanced Evans Blue leakage and mucus release in the perfusate after intraluminal challenge with ovalbumin in ovalbumin-immunized rats, but not in non-immunized rats. A significant increase of BTB binding with macromolecular substances in the perfusate was observed during the local anaphylaxis. These findings suggest that the decreased absorption of BTB is due to the interaction with the macromolecular substances in the perfusate during local anaphylaxis.

Anaphylaxis↗
PubMed1986

Effect of temperature on intestinal transfer and tissue uptake of sulfanilamide and aminopropyron in vitro.

The effect of temperature on the transfer and the tissue uptake of sulfanilamide and aminopropyron, an aminopyrine derivative, was investigated using the everted and the non-everted sacs of rat intestine. The M (mucosa) to S (serosa) transfer of sulfanilamide was slightly faster than reverse S-to-M in the ileum at the temperatures studied. Decreased transfer and tissue uptake of sulfanilamide with decreasing temperature were observed using both ileal everted and non-everted sacs. On the contrary, the M-to-S transfer of aminopropyron was slower than the S-to-M transfer in the ileum. The tissue uptake of aminopropyron was almost constant at any temperature in the ileal non-everted sac experiments, while a decreased transfer of aminopropyron was observed with a decrease in temperature. Similar results, like aminopropyron in the ileum, were obtained in the experiments of aminopropyron and sulfanilamide using the colonic sacs. It is concluded that a close relationship may exist between the directional superiority in the transfer and the temperature independency of the tissue uptake.

Aminopyrine↗
PubMed1986

Effect of medium-chain glycerides (MGK) on the intestinal absorption and the hepatobiliary transport of bromthymol blue.

The effect of medium chain glyceride (MGK) emulsion on the intestinal absorption and the biliary excretion of bromthymol blue (BTB) was investigated in rats. Extensive tissue accumulation of BTB was reduced when BTB was administered with MGK emulsion formulation. HCO-100, an emulsifier, was also important for the decrease in the tissue accumulation of BTB. The ratios of absorption percent to tissue accumulation percent and to free fraction, not contained in the droplet of emulsion, in MGK emulsion were much greater than that of the control. Pretreatment with BTB-free emulsion reduced BTB absorption under the control, although tissue accumulation was not affected. The absorption appeared to decrease with increase in the time of pretreatment. The effect of leaving treatment after pretreatment on the absorption of BTB was also investigated. With the increase in leaving time after pretreatment, reduced absorption tended to resume to the level of control. The change in monocaprylate content from 54 to 60% in MGK made a difference in BTB absorption and it was suggested that monocaprylate content in MGK was one of the significant factors of MGK emulsion on drug absorption. Bile recovery study was simultaneously carried out with an in situ recirculation experiment. The recovery of BTB into bile tended to decrease. The ratio of recovery percent of BTB into bile to the absorption percent of BTB also decreased extensively, which is possibly another effect of MGK on drug disposition.

Animals↗
PubMed1986

Cellular interaction and in vitro antitumor activity of mitomycin C-dextran conjugate.

Cellular interaction and in vitro antitumor activity of a polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D), were studied in relation to its physicochemical characteristics. MMC-D with cationic and anionic charges were examined. The cationic MMC-D was synthesized using a spacer, epsilon-aminocaproic acid and dextrans with molecular weights of 10,000, 70,000, or 500,000 [MMC(C6)Dcat]. The anionic MMC-D was synthesized using 6-bromohexanoic acid as a spacer and dextran with a molecular weight of 70,000 [MMC(C6)Dan]. Cellular adsorption was determined by measuring the concentration of the drug in the medium after incubation with three tumor cell lines, Ehrlich ascites carcinoma, L1210 leukemia, and AH66 ascites hepatoma cells. MMC(C6)Dcat was adsorbed more readily than MMC or MMC(C6)Dan on the tumor cell surface by an electrostatic force. The percentage of adsorption remained almost constant during the course of incubation and no significant difference was observed between the incubation at 4 degrees C and that at 37 degrees C. A corresponding increase in the amounts of MMC(C6)Dcat adsorbed on with higher molecular weights was noted, which conformed to Langmuir's adsorption isotherm. In vitro antitumor activity was evaluated using L1210 and EAC cell culture systems and human tumor colony forming assay. MMC(C6)Dcat showed growth inhibition essentially equal to that of MMC in continuous drug exposure experiments. In a 1-h drug exposure experiment, MMC(C6)Dcat with a molecular weight of 70,000 or 500,000 was more active than MMC, and a good correlation was observed between the effects of MMC(C6)Dcat and the extent of cellular interaction. These results show that cellular interaction played an important role in the manifestation of the antitumor effect of MMC-D and that these phenomena are governed by the physicochemical properties of macromolecular prodrugs, such as electric charge and molecular weight.

Adsorption↗
PubMed1985

A new method for assessment of drug disposition in muscle: application of statistical moment theory to local perfusion systems.

A new experimental system is used to determine exact information concerning local drug disposition. Rabbit hind leg is perfused in situ using a single-pass technique, and outflow curves of drugs are analyzed using statistical moment theory. By the introduction of chromatographic concepts and the application of the well-stirred model to the local perfusion system, physiologically and/or physicochemically meaningful parameters are derived from the first three moments. Moreover, in the assessment, drug disposition is divided into elimination and distribution. The elimination process is also evaluated with respect to rate and extent. This system is used to elucidate the disposition characteristics of mitomycin C and its lipophilic derivative nonyloxycarbonyl mitomycin C.

Animals↗