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Biomedical subjects

M Hashida

Publications and source records attributed to M Hashida.

At least 109 records · Page 6Linked to original sources
PubMed1988

Analysis of drug penetration through skin considering donor concentration decrease.

A diffusion model for in vitro drug penetration through the skin was constructed which considered drug concentration decrease in the donor solution. The Laplace transforms of the equations corresponding to the time courses of the drug amount in the receptor solution, in the skin and in the donor solution were derived. Computer fitting of the penetration profiles of in vitro experiments to the obtained Laplace transformed equation by a non-linear least squares program based on first inverse Laplace transform algorithm (MULTI(FILT)) gave two parameters corresponding to drug diffusion and partitioning. These parameters well estimated the drug amount remaining in the donor solution and in the skin. The mean transit time (MTT) was defined for drug penetration through the skin and was calculated using these parameters. MTT was shown to be a good index of drug penetrability.

Animals↗
PubMed1988

Right ventricular aneurysm due to congenital muscular defect in an adult.

A large right ventricular aneurysm was detected by an echocardiographic examination in a 50-year-old woman presenting with weakness, collapse and hypotension. At surgery, another smaller aneurysm, arising from the anterior infundibulum of the right ventricle, was found in addition to the large one. Both were resected. Histological studies on the resected specimen revealed that much of the myocardium was replaced by adipose tissue. As far as we know this is the first reported case in Japan in which two congenital aneurysms arose from the right ventricle as a result of muscular defect.

Adipose Tissue↗
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↗