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Biomedical subjects

M Hashida

Publications and source records attributed to M Hashida.

At least 55 records · Page 3Linked to original sources
PubMed1988

Structure-activity relationship of 1-alkyl- or 1-alkenylazacycloalkanone derivatives as percutaneous penetration enhancers.

Nine azacycloalkanone (5-, 6-, or 7-member ring) derivatives with an alkyl or alkenyl (terpene) chain (10, 15, or 20 carbons) were compared with 1-dodecylazacycloheptan-2-one (azone, 1) for their effects on the percutaneous penetration of 6-mercaptopurine (6-MP) through excised guinea pig skin. Pretreatment of skin with an enhancer markedly increased penetration and skin accumulation of 6-MP. Superior enhancing effects were observed for enhancers having a terpene chain of 10 carbons and an azacyclo ring with one carbonyl group. Enhancers with a C20 tail chain were less effective. Enhancer ring size had little effect on enhancing activity, whereas the increase in the number of carbonyl groups in the ring caused a decrease. Computer fitting of a penetration profile to Fick's diffusion equation gave two parameters corresponding to diffusion and partitioning of 6-MP. The diffusion parameter was little affected by pretreatment with an enhancer, whereas the partition parameter was markedly increased. This suggests that enhancement is determined by the ability to increase the drug partitioning into the skin and to enlarge the drug concentration gradient in the skin barrier. The primary skin irritation was examined with rabbit dorsal skin in vivo. The enhancers with an alkyl chain induced severer primary irritation (erythema and edema) than those with an alkenyl chain. From the balance between enhancing and irritating activities, it is concluded that 1-geranylazacycloheptan-2-one, 1-farnesylazacycloheptan-2-one and 1-farnesylazacyclopentan-2-one are favorable enhancers.

Animals↗
PubMed1988

Effect of plasma protein binding on drug disposition in muscle tissue: application of statistical moment analysis and network theory to in situ local single-pass perfusion system.

The local disposition characteristics of mitomycin C (MMC) and five lipophilic prodrugs in rabbit hind leg muscle were examined using an in situ single-pass perfusion experiment. Test compounds inputted into a perfusion line as a rectangular function (unit pulse) were perfused with or without albumin and their outflow patterns were analyzed by statistical moment analysis. In interpretation of statistical moment parameters, the well-stirred model was applied to the local perfusion system based on the plate theory of a chromatographic system and some general pharmacokinetic parameters (the disposition parameters) were derived from the moments. A new theory which elucidates the relationships among the moments for plasma protein binding, unbound (free), and total drug fraction was established based on network theory. Using this system, the following conclusions were made for mitomycin C and its five lipophilic derivatives: (i) In the absence of albumin, an increase in lipophilicity led to an increase in organ clearance and distribution volume; (ii) drug bound to albumin did not transfer to the extravascular space; (iii) in the presence of albumin, an increase in lipophilicity results in a decrease in clearance.

Animals↗
PubMed1988

Enhanced membrane permeability to phenol red by medium-chain glycerides: studies on the membrane permeability and microviscosity.

To clarify the mechanism of the drug absorption enhancement by medium-chain glycerides (MCG), the changes in membrane permeability provoked by MCG were investigated with liposomal uptake experiments. Uptake of phenol red (PR) into liposomes increased with an increase in MCG content in the liposomal membrane, suggesting that PR absorption was enhanced in the "transcellular route." However, the apparent membranous microviscosity obtained in fluorescence depolarization studies tended to increase with the addition of MCG in both the hydrophobic core and the polar head regions of the liposomal membrane. Thus, an enhancement in membrane permeability caused by MCG was not accompanied by a decrease in the apparent membranous microviscosity.

Absorption↗
PubMed1988

The accumulation mechanism of cationic mitomycin C-dextran conjugates in the liver: in-vivo cellular localization and in-vitro interaction with hepatocytes.

To elucidate the mechanism of the accumulation of mitomycin C-dextran conjugate (MMC-D) in the liver, in-vivo cellular uptake and in-vitro cellular interaction of MMC-D have been studied. Localization of cationic and anionic MMC-D (MMC-Dcat. and MMC-Dan.) in different liver cell types following i.v. administration was examined in rats and the significant contribution of parenchymal cells demonstrated. In-vitro cellular interaction was determined by measuring the drug concentration in the medium after incubation with rat isolated hepatocytes. MMC-Dcat. was highly adsorbed on the surface of hepatocytes at pH 7.2, while the interaction between MMC-Dan. and hepatocytes was negligible. The percentage association of MMC-Dcat. with hepatocytes remained almost constant during the course of incubation and no significant difference was observed between the incubation at 4 and 37 degrees C. The adsorption phenomenon was shown to conform to Langmuir's adsorption isotherm. The amount of MMC-Dcat. associated with hepatocytes increased as the molecular weight of the dextran chain increased. These results showed that MMC-Dcat. was adsorbed on the surface of hepatocytes by an electrostatic force and this binding was responsible for its remarkable accumulation in the liver in-vivo. Thus some physicochemical properties of the MMC-D conjugates are thought to play an important role in the disposition characteristics of the conjugates.

Animals↗
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↗