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Biomedical subjects

M Hashida

Publications and source records attributed to M Hashida.

At least 217 records · Page 12Linked to original sources
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↗
PubMed1985

Absorption characteristics of the lipophilic prodrug of mitomycin C from injected liposomes or an emulsion.

Mitomycin C (MMC) is amphiphilic and so cannot be incorporated into lipoidal delivery systems. To develop a lipoidal delivery system, its prodrug, nonyloxycarbonyl MMC, was formulated in liposomes and in o/w emulsions and the usefulness of these formulations was evaluated. After injection into the rat thigh muscle, MMC was rapidly absorbed regardless of the dosage form. However, the prodrug was retained at the injection site for considerably longer when formulated in a lipid dispersion system. The accumulation of MMC at regional lymph nodes was also investigated and whereas free MMC arrived at and disappeared from the lymph nodes almost immediately after injection, the prodrug arrived at an early stage and its concentration decreased only gradually, remaining fairly high 2 h after injection. Liposomal lipids appeared to accumulate at the lymph nodes to a greater degree than o/w emulsions. It is suggested that the combination of lipidic carrier devices with lipophilic prodrugs may be a useful adjunct to cancer chemotherapy.

Absorption↗
PubMed1985

Enhanced delivery of mitomycin C derivatives through hairless mouse and rat skins.

The percutaneous permeation characteristics of two lipophilic mitomycin C derivatives with aromatic moieties were determined using excised hairless mouse and rat skins and compared with those of mitomycin C (MMC). 1a-N-Benzylmitomycin C penetrated more readily through both kinds of skin than MMC without metabolic conversion. 1a-N-Benzyloxycarbonylmitomycin C effected a 4-fold increase in the delivery of MMC through the rat skin and was completely converted to MMC by an enzyme in rat skin. However, saturation of the metabolic conversion activity was observed in the hairless mouse skin.

Administration, Topical↗
PubMed1985

Urinary excretion characteristics of a polymeric prodrug of mitomycin C, mitomycin C-dextran conjugate.

Urinary excretion characteristics of a polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D), following intravenous administration was studied in rats. Three types of MMC-D, conjugates with dextrans of molecular weights of 10000, 70000 and 500000, were tested and urine concentration of MMC, dextran and spacer were determined by three analytical methods, i.e., bioassay, anthrone method and radioactivity counting. MMC was assayed separately as a free form and conjugated form based on antimicrobiological activity. MMC administered as a free form was excreted rapidly into urine but only a small amount of MMC was excreted following the administration of MMC-D. The excreted amount of MMC in a conjugated form varied with the size of carrier dextran while similar sustained excretion was observed regardless of the carrier size. The excretion of carrier dextran determined by anthrone method was confined as the molecular weight was increased. The effect of molecular weight was also observed in the case of spacer-introduced dextran (dextran-C6 spacer) and original dextran. Compared with neutral dextran, cationic MMC-D and anionic dextran-C6 spacer exhibited diminished excretion, indicating the effect of charge on urinary excretion. The urinary recovery of radioactivity was almost in accordance with that of carrier dextran. However, the urinary recovery of MMC based on biological activity was considerably lower than that of carrier dextran. It was suggested that MMC-D underwent inactivation to a great extent before releasing active MMC in the body. The effect of physicochemical properties such as molecular weight and electric charge on the urinary excretion of the polymeric prodrug was thus elucidated.

Animals↗
PubMed1985

Immunological control of drug absorption from the gastrointestinal tract: effect of local anaphylaxis on the intestinal absorption of low molecular weight drugs in the rat.

Intestinal absorption of various drugs was examined by means of in situ recirculation technique during local anaphylaxis. The antibody was determined by passive cutaneous anaphylaxis technique in rats immunized once or three times. The optimal condition of local anaphylaxis was determined by the leakage of Evans Blue. The most significant increase in leaks of the dye was observed by the intraluminal challenge with 400 mg of ovalbumin for 10 min in ovalbumin-immunized rats, and this condition was chosen as the optimal condition of local anaphylaxis. Under this condition, intestinal absorption of caffeine, phenylbutazone, and bromthymol blue (BTB) significantly decreased in ovalbumin-immunized rats compared with the control, whereas no significant effect was noted in the intestinal absorption of salicylic acid, quinine, pralidoxime iodide (2-PAM), tetracycline, and phenol red. In normal rats, no significant decrease was obtained in the intestinal absorption of caffeine, phenylbutazone, and BTB. On the other hand, the decreased absorption of BTB was not found in ovalbumin-immunized rats by the intraluminal challenge with bovine gamma-globulin. Furthermore, there was no significant change in the decreased absorption of BTB between rats immunized once and three times. The most effective condition for decreased BTB absorption was observed by the intraluminal challenge with 200 mg of ovalbumin for 10 min in ovalbumin-immunized rats, which almost correlated with the data of Evans Blue leakage. From these observations, it appears that the mucosal immune responses affect the intestinal absorption of low molecular weight drugs.

Anaphylaxis↗
PubMed1985

[Topical application of mitomycin C conjugated with dextran (MMC-D): a high molecular weight derivative of mitomycin C].

Mitomycin C conjugated with dextran (MMC-D), with a molecular weight of about 500,000, was synthesized for intraoperative topical application. MMC-D contained approximately 10% mitomycin C (MMC) and released active MMC by hydrolysis with a half-life of 24 hours in vivo. In experimental studies, MMC-D was retained at the injection site for about 48 hours and transferred to the lymphatic system. Sixteen patients suffering from advanced abdominal cancers were treated with MMC-D (5-10mg eq. MMC) by intraoperative direct injection or percutaneous injection under sonography. Objective tumor responses were observed in 9 of 16 cases. No serious side-effect was observed other than temporary fever, localized pain and mild leukopenia. MMC-D diffused from the center of the tumor releasing active MMC which was transferred to the lymphatic system. Local application of MMC-D was therefore considered to be effective for the treatment of solid tumors.

Aged↗
PubMed1984

Antitumor activity of lipophilic prodrugs of mitomycin C entrapped in liposome or O/W emulsion.

Nine lipophilic la-N-substituted prodrugs of mitomycin C were formulated in lipid dispersion dosage forms and their fundamental antitumor activities were evaluated. The prodrugs were efficiently incorporated into liposome or O/W emulsion according to their increased lipophilicities , while mitomycin C was hardly entrapped into them. Almost complete incorporation was observed in nonyloxycarbonyl and cholesteryloxycarbonyl mitomycin C which showed partition coefficients over 8000 in chloroform/water system. The release rate from these dosage forms determined by a dynamic dialysis method decreased with an increase in the partition coefficients of the derivatives. All prodrugs entrapped in liposome or O/W emulsion showed significant antitumor activities against L1210 leukemia in i.p.-i.p. system except for cholesteryloxycarbonyl mitomycin C. In spite of considerable antitumor activities showen in the forms of liposome and emulsion, saline suspension of nonyloxycarbonyl mitomycin C failed to exhibit any activity because of its poor aqueous solubility. These results suggested the utility of the combining delivery system of lipophilic prodrug with physical device such as liposome and O/W emulsion.

Animals↗
PubMed1984

Drug absorption from the gastrointestinal tract and immunity: the mechanism of the decreased absorption of salicylic acid during systemic anaphylaxis. I.

Previous studies have demonstrated the decrease of intestinal salicylic acid absorption in ovalbumin-immunized rats during systemic anaphylaxis. In the present study, the mechanism whereby systemic anaphylaxis interferes with the intestinal absorption of salicylic acid was studied. The pH of the luminal solution was not affected by the intravenous challenge with ovalbumin. A significant increase of the intraluminal protein was observed in rats under systemic anaphylaxis. However, there was no significant difference between ovalbumin-treated rats and saline-treated ones on the binding of salicylic acid with intraluminal macromolecular substances. Enhanced mucus release in the perfusate was also observed in sensitized rats but the extent of decrease in absorption of salicylic acid did not correlate with the increase in amount of the intraluminal mucus in the same animals. In addition, no significant effect was observed on the uptake by the intestinal everted sac of rats with systemic anaphylaxis. These findings suggested that mucus as well as protein is not responsible for the decrease of absorption of salicylic acid induced by systemic anaphylaxis. From these observations, it would appear that the circulatory changes in the gastrointestinal tract may play an important role in the decreased absorption of salicylic acid during systemic anaphylaxis.

Anaphylaxis↗
PubMed1984

Drug absorption from the gastrointestinal tract and immunity: the mechanism of the decreased absorption of salicylic acid during systemic anaphylaxis. II.

Rats were intraperitoneally immunized with ovalbumin (egg albumin) with incomplete Freund's adjuvant, and the effect of intravenous challenge with ovalbumin on the intestinal blood flow was measured by means of hydrogen clearance method. The intestinal blood flow was significantly reduced by the antigen challenge in ovalbumin-immunized rats compared to the non-immunized rats. However, no significant change was observed on the intestinal blood flow in rats without challenge of the antigen. Moreover, the blood flow reduction was not found in ovalbumin-immunized rats challenged with bovine gamma-globulin. The effect was maintained for at least 16 weeks after the third immunization, but the reduced blood flow was gradually restored to the control level. The decrease in both blood flow and absorption of salicylic acid was recovered by nearly 70% of the control level when high dose of theophylline or caffeine was administered intravenously. In the case of gastric absorption during systemic anaphylaxis, similar results were also obtained by means of in situ loop technique. The decreased absorption of salicylic acid from the rat stomach also correlate with the reduced gastric blood flow. These findings suggest that the decreased absorption of salicylic acid from the gastrointestinal tract might be affected by the reduced blood flow during systemic anaphylaxis.

Anaphylaxis↗