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Biomedical subjects

M Hashida

Publications and source records attributed to M Hashida.

At least 91 records · Page 5Linked to original sources
PubMed1987

Disposition characteristics of mitomycin C-dextran conjugate in normal and tumor-bearing muscles of rabbits.

Disposition characteristics of the macromolecular prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D), in normal and tumor (VX2 carcinoma)-bearing rabbit thigh muscles were studied using the in situ vascular perfusion technique. Three types of cationic MMC-D (MMC-Dcat) and two types of anionic MMC-D (MMC-Dan) with different carrier molecular weights were used. After bolus arterial injection in normal muscles, 83-96% of injected MMC-D was recovered in the venous outflow regardless of the carrier size or charge, whereas less than 60% of MMC was recovered in the same system. By applying statistical moment analysis to the outflow pattern of these drugs, pharmacokinetic parameters representing their disposition characteristics were obtained. Smaller intrinsic clearance (CLint) and distribution volume (V) were noted for MMC-D than for MMC, indicating low extravascular diffusion of MMC-D. In the tumor-bearing muscle, blood contamination from other parts of the body increased and a shortage of flow recovery due to the neovascularization of the tumors occurred. The disposition parameters of MMC-Dcat with a molecular weight of 500,000 (T-500) indicated some tissue distribution and sequestration in the tumor preparation. After constant infusion of [14C]MMC-D (T-500) for 4 h, tissue radioactivity concentrations were determined in various tissues. A higher radioactivity was observed in the viable region of the tumor and the lymph node compared with the normal muscle tissue and the necrotic region of the tumors. 131I-Labeled human serum albumin also gave similar results. In conclusion, higher tumor localization of antitumor agents may be made possible by the application of macromolecular prodrugs.

Animals↗
PubMed1987

Treatment of cystic hygroma and lymphangioma with the use of bleomycin fat emulsion.

Of the several types of treatment for cystic hygromas and lymphangiomas, surgical excision has been the preferred treatment. However, there is a high recurrence rate because lymphangiomas tend to infiltrate the surrounding tissues. Bleomycin in a microsphere-in-oil (S/O) emulsion was used in this study as a sclerosing agent for lymphangiomas. Experimental studies using domestic rabbits showed that the bleomycin emulsion caused more marked fibrotic changes at the injection site than other formulations, such as a blank emulsion and bleomycin solution. In clinical trials, 27 of 33 patients received bleomycin S/O emulsion injected directly into the tumors with satisfactory results. Histologic pictures of the clinically resected specimens confirmed the findings of the experimental studies. Comparative studies of treatments between bleomycin S/O emulsion and surgery indicated that injection therapy of bleomycin S/O emulsion would be more beneficial than surgical excisions.

Animals↗
PubMed1987

Decreased transport of D-glucose and L-alanine across brush-border membrane vesicles from small intestine of rats treated with mitomycin C.

To elucidate the mechanisms underlying the dysfunctions of intestinal absorption induced by antitumor drugs, the effect of pretreatment with mitomycin C on sodium gradient-dependent D-glucose and L-alanine transports was studied in rat brush-border membrane vesicles. 24, 48, 96, or 120 h following a single intravenous injection of mitomycin C, brush-border membrane vesicles were prepared from rat small-intestines. The uptake of D-glucose and L-alanine was shown to be Na+ gradient-dependent even in the case of vesicles obtained from mitomycin C-treated rats, but uptake rates measured at 15 s and magnitude of overshooting effect in uptake of both solutes were decreased in vesicles maximally from 48 h mitomycin C-treated rats. The rate of D-glucose uptake calculated at 15 s recovered to the control level in vesicles prepared at 96 h and 120 h after mitomycin C-treatment, indicating that the effect of mitomycin C on Na+ gradient-dependent D-glucose transport would be fully reversible. Tracer exchange experiments under Na+ and D-glucose equilibrated conditions indicated that the Na+/D-glucose transporters were similarly operative in the vesicles from control and 48 h mitomycin C-treated rats. Rates of 22Na+ uptake measured at 15 s in vesicles from 48 h mitomycin C-treated rats, however, were increased. The increased permeability to Na+ might bring about a more rapid dissipation of the Na+ gradient in these vesicles and this would secondarily cause the decrease in Na+-dependent D-glucose uptake in vesicles from mitomycin C-treated rats.

Alanine↗
PubMed1987

Disposition and tumor localization of mitomycin C-dextran conjugates in mice.

Mitomycin C-Dextran conjugates (MMC-D) were intravenously (iv) injected in mice bearing subcutaneous sarcoma 180. The tissue distribution was determined for three 14-C-labeled anionic conjugates (MMC-Dan) with molecular weights of 10, 70, and 500 kd and one cationic 70-kd 14C-conjugate (MMC-Dcat). The anionic conjugates were slowly cleared from the plasma, and their elimination rate decreased with increasing molecular weight. Radioactivity accumulated in liver, spleen, lymph nodes, and tumor but not in heart, lung, intestines, kidney, or muscle after iv injection of all types of 14C-MMC-Dan. In contrast, the cationic conjugate was rapidly cleared from the plasma and accumulated mostly in the liver and spleen, while tumor levels remained low. The antitumor effect of the 70-kd MMC-Dan, which afforded the highest tumor concentration, was superior to that of free MMC. Therefore, anionic mitomycin C-dextran conjugates with a high molecular weight may be useful for tumor targeting in cancer chemotherapy.

Animals↗
PubMed1987

Enhanced penetration of mitomycin C through hairless mouse and rat skin by enhancers with terpene moieties.

The effects of four new percutaneous absorption enhancers containing an azacyclo ring and terpene chain (1-geranylazacycloheptan-2-one (GAH), 1-farnesylazacycloheptan-2-one (FAH), 1-geranylazacyclopentan-2,5-dione (GAPD), and 1-farnesylazacyclopentan-2-one (FAP] and 1-dodecylazacycloheptan-2-one (Azone) on the percutaneous penetration of mitomycin C (MMC) through hairless mouse and rat skin in-vitro has been investigated. GAH, FAH, FAP and Azone enhanced MMC penetration by 20 to 60 times that of the control (ethanol). During the early part of the experiments, when the sink condition was maintained, FAH was the most effective for hairless mouse skin, whereas Azone showed the highest effect in the rat skin. The enhancing effect of GAPD was only about half that of the other enhancers, suggesting the importance of the polar group of the ring moiety in these compounds. The penetration of MMC through rat skin was also increased by pretreatment with these compounds, suggesting that the enhancers had a direct effect on the skin.

Animals↗
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↗