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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
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↗
PubMed1984

Macromolecule-drug conjugates in targeted cancer chemotherapy.

Although clinical trials using macromolecular conjugates of cytotoxic drugs in a treatment of malignant disease are fragmentary at best, a number of carrier systems that have been examined in vitro, in tissue culture, and in vivo animal experiments demonstrate great promise and warrant further extensive examination. The optimal drug delivery and, consequently, maximum therapeutic effect will be accomplished when all available information from diverse disciplines can be integrated. This review has attempted to point out some of the limitations of taking an optimistic view of the question of targeting drug delivery using macromolecule-drug conjugates. For example, a strategy for the development of macromolecular conjugates can be established based on characteristics of the targeted tumors and the drugs in prospect of great success. Biological and physiological features of the tumor such as a cell type, site, and the pharmacological and physicochemical properties of chemical agents such as site of action and chemical stability must be considered at the first step. Selection of the optimum carrier system will be accompanied when all these problems are carefully considered. Similarly, the optimum method of conjugation is likely to vary as a function of the carrier, the chemotherapeutic agent, and the delivery site or site of action of the agent. The stability of the bond must adopt itself to the mode and site of action of the agent, the necessity for release, and the availability of hydrolytic enzymes which break the linkage and release the agent. On the other hand, the success of such conjugates synthesized according to this strategy will depend on physicochemical properties of the conjugates such as molecular size, electric charge, and solubility; chemical and biological stability of active components of conjugates and linkages; interaction with the tumor cells; cytotoxicity in tissue culture system; pharmacokinetics in the body such as absorption profile, localization, and elimination manner; in vivo antitumor activity; and biodegradability and antigenicity of the conjugates. The practitioners of macromolecular conjugate research find themselves in the interesting, but difficult, position of being at the interface between basic information on the drugs and biological systems and an expanding clinical demand for more sophisticated therapeutic agents. Consequently, knowledge is demanded not only of the chemical, physical, and pharmaceutical properties of macromolecules, but also of pathophysiology of the condition being treated.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Enhanced lymphatic delivery of mitomycin C conjugated with dextran.

Absorption and lymphatic transfer of a polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D), following i.m. injection were studied in rats in order to assess the feasibility of a macromolecular prodrug as a lymphotropic delivery system. Three types of MMC-D, conjugates with dextran with molecular weights of 10,000, 70,000 and 500,000, were synthesized, and the disposition of MMC was determined by bioassay. Following i.m. injection of MMC-D, MMC was retained at the injection site for a long period in a conjugated form while MMC administered as a free form disappeared rapidly. The disappearance was markedly influenced by the size of carrier dextran, because the remaining amount of MMC increased with an increase of molecular size. The lymphatic uptake of the drug was evaluated by determining the concentration in the regional lymph nodes and thoracic lymph fluid. In contrast to a slight lymphatic uptake following i.v. and i.m. injection of free MMC, MMC-D exhibited remarkable accumulation in the regional lymph nodes after i.m. injection which persisted up to 48 hr. MMC-D (Mr 10,000) appeared in the thoracic lymph as both the conjugated and the free form. Larger MMC-D gave a persistent supply of free MMC in thoracic lymph, suggesting that it was accumulated in the lymph node and supplying MMC continuously. These MMC-Ds suppressed the lymph node metastases introduced by a s.c. inoculation of L1210 leukemia cells. The usefulness of MMC-D as a lymphotropic delivery system for preventing lymphatic metastasis of cancer was suggested.

Animals↗
PubMed1984

[Local administration of anti-cancer drugs].

Anti-cancer drugs in the forms of an emulsion, a microsphere, and of conjugates with high molecular dextran have been developed in our laboratories, namely a fat emulsion of anticancer drug, MMC-microsphere, or MMC-dextran conjugates. The main advantages of these forms of pharmaceutical preparation are that they give prolongation of pharmacological actions by slow release and that they are applicable for topical use because of their reduced toxicities to local tissue yet maintaining local therapeutic potency. In this study we found that the rate of sustained release of drugs and antitumor effects were enhanced when used in such modified forms of drugs for topical injections. Results of clinical trials of those drugs have been promising. However, the number of trials has been limited so far. Further studies would be required for evaluating on of their clinical utilities.

Adult↗
PubMed1983

Prodrugs of 6-thiopurines: enhanced delivery through the skin.

Soft-alkylated derivatives of 6-mercaptopurine, its riboside, and 2-amino-6-mercaptopurine riboside have been prepared and evaluated to improve the delivery of the thiopurines through the skin. The soft-alkylated derivatives were prepared by the alkylation of the thiopurines with acylheteroalkyl halides under neutral or basic conditions. The penetration of the derivatives through hairless mouse skin was measured using diffusion cells. All of the derivatives underwent extensive degradation during their diffusion through skin so that the parent thiopurine, even in the case of the ribosides, was the major product observed in the receptor phase. The pivaloyloxymethyl derivatives showed the greatest potential for enhancing the penetration of the thiopurines through the skin. Among the 6-mercaptopurine derivatives, VII and XI were the most effective; they delivered 5 and 13 times, respectively, more 6-mercaptopurine than 6-mercaptopurine itself.

Animals↗
PubMed1981

Antitumor activity of mitomycin C-dextran conjugate against various murine tumors.

The antitumor activity of a high molecular weight pro-drug of mitomycin C(MMC), MMC-dextran conjugate (MMC-D), was examined against various murine tumors under different experimental conditions. A single intraperitoneal injection of MMC-D exhibited higher antitumor activity against intraperitoneally inoculated B16 melanoma, Ehrlich ascites carcinoma, and P388 leukemia than MMC, but lower activity against BDF1 mouse-transplanted L1210 leukemia. Intratumoral injection of MMC-D showed a superior effect on subcutaneously implanted B16 melanoma, while intravenous injection of MMC-D exhibited reduced activity against P388 and L1210 leukemia compared with MMC. Prior administration of MMC-D at 24 hr before tumor inoculation resulted in a significant increase of the life span of mice bearing L1210 leukemia, suggesting that it shows sustained pharmacological activity. These differences between the activities of MMC-D and MMC in various tumor systems are considered to reflect the improved biopharmaceutical properties of MMC-D resulting from the modification of MMC into a polymeric drug.

Animals↗