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Biomedical subjects

M Hashida

Publications and source records attributed to M Hashida.

At least 73 records · Page 4Linked to original sources
PubMed1989

Disposition of a polymeric prodrug of mitomycin C, mitomycin C-dextran conjugate, in the perfused rat liver.

The disposition of a polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D), was studied in the single-pass perfused rat liver in order to clarify the effect of physico-chemical properties, such as molecular weight and electric charge, on the hepatic uptake of MMC-D. Six types of MMC-D were used: both cationic MMC-D (MMC-Dcat) and anionic MMC-D (MMC-Dan) conjugated with dextran with molecular weights of 10,000, 70,000, and 500,000. Outflow curves were analyzed using statistical moment theory. Remarkable hepatic uptake of MMC-Dcat was observed and the uptake amount increased with an increase in molecular weight (i.e., approximately 80% of the dose was taken up by the liver during a single passage of the conjugate with a molecular weight of 500,000). Intrinsic clearance (CLint,i) and apparent distribution volume (Vi) also increased as the molecular weight increased. On the other hand, almost 100% of applied MMC-Dan was recovered in the outflow regardless of molecular weight, with almost the same moment parameters as those of the vascular reference substance (VRS), 131I-labeled human serum albumin (HSA). In a repeated application, the uptake of MMC-Dcat decreased in a stepwise manner, suggesting a saturation in the hepatic uptake of MMC-Dcat, while the uptake of MMC-Dan was unchanged. The MMC-Dcat pretreatment also affected the uptake of Evans blue (EB) bound to bovine serum albumin (BSA). These results demonstrate that molecular weight and electric charge determine the hepatic disposition of macromolecular prodrugs.

Animals↗
PubMed1989

Control of pharmaceutical properties of soybean trypsin inhibitor by conjugation with dextran. I: Synthesis and characterization.

The Kunitz-type soybean trypsin inhibitor (STI), a model protein, was conjugated with dextran (Mw, approximately 9900; STI-D), and its physicochemical and biochemical properties were studied to develop a novel delivery system for a protein drug. Conjugation was carried out using periodate oxidation, and cyanogen bromide, carbodiimide, cyanuric chloride, epichlorhydrin, and N-succiniimidyl-3-(2-pyridyldithio)propionate (SPDP) reagent methods. Dextran was conjugated to STI at a molar ratio of 1.5 to 4.6, but the degree of modification, as well as yield and contamination extent of unreacted STI and dextran, varied with the method of synthesis. Gel filtration and electrophoresis confirmed the covalent attachment of dextran to STI but also demonstrated the broad molecular weight distribution of the conjugates. The STI-D conjugate retained satisfactory activity, although the attachment partially reduced its inhibitory activity against trypsin. The periodate oxidation method seemed to be the best for the preparation of STI-D since it gave the conjugate with a high modification ratio (4.6 molecules per STI), high yield (95%), and satisfactory activity recovery (63%). Chemical modification of STI was also carried out with activated polyethylene glycol (PEG) for comparison. The STI-PEG conjugate was obtained in a satisfactory yield (96%) and modification degree (5.8 molecules per STI), but the remaining activity was considerably lower (34%). Thus, conjugation of protein with dextran by the periodate oxidation method is suggested to be preferable for preparing a protein-carrier system without significant diminution of its biological activity.

Carbodiimides↗
PubMed1989

Control of pharmaceutical properties of soybean trypsin inhibitor by conjugation with dextran. II: Biopharmaceutical and pharmacological properties.

Biopharmaceutical and pharmacological properties of the Kunitz-type soybean trypsin inhibitor (STI)-dextran conjugate (STI-D) were studied. Dextran having a molecular weight of approximately 10,000 was covalently attached to the STI molecule by periodate oxidation. The STI-polyethylene glycol (PEG) conjugate (STI-PEG) was also tested for comparison. After iv injection to mice, native STI showed rapid elimination of activity from plasma (t 1/2 = 2 min), and approximately 60% of the dose was excreted in urine within 1 h after injection. On the other hand, STI-D was slowly cleared from plasma and its urinary excretion was restricted. The STI-PEG conjugate showed a pharmacokinetic behavior similar to that of STI-D. Pharmacological activities of native and modified STI were evaluated by two animal experimental models; that is, trypsin-induced shock in mice and acute pancreatitis in rats. In mice, shock induced by iv injection of trypsin was inhibited by the iv pretreatment with native STI, but the effect was observed for only 1 h. The STI-D conjugate showed a superior inhibitory effect on trypsin-induced shock to that of STI alone at the same dose, and this effect continued for 5 h. A similar effect was also observed in mice given an iv injection of STI-PEG. In rats with acute pancreatitis, no significant therapeutic effect was shown by the iv treatment with native STI, as well as saline treatment. On the other hand, the iv treatment with STI-D at the same dose as STI lowered the mortality of the rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The effect of immunization with protein-hapten conjugate on the intestinal uptake of p-aminobenzoic acid as a hapten.

Intestinal uptake of p-aminobenzoic acid was examined by means of an in vitro everted sac technique in rats immunized with ovalbumin-p-aminobenzoic acid conjugate. A dose-dependent and antigen-specific decrease in the serosal transfer of p-aminobenzoic acid was observed in rats immunized 6 times with protein-hapten conjugate compared with the control. There was a significant increase in the recovery of p-acetamidobenzoic acid, a metabolite of p-aminobenzoic acid, in mucosal fluid, tissue, and serosal fluid in the jejunum. In the case of ileum, increase of p-acetamidobenzoic acid was observed in mucosal fluid. However, there was no significant effect in the ileal p-acetamidobenzoic acid in tissue and serosal fluid between immunized and non-immunized rats. To examine the increased metabolism of immunized rats, N-acetyltransferase activity of the small intestinal mucosa was examined. There was a significant increase in mucosal N-acetyltransferase activity in immunized rats compared with the control animals. These observations suggested that the mucosal immune system may play an important role in regulating the intestinal uptake of the low molecular weight compounds.

4-Aminobenzoic Acid↗
PubMed1989

Statistical moment analysis of hepatobiliary transport of phenol red in the perfused rat liver.

A new experimental system was applied to study hepatobiliary transport of drugs. Rat livers were perfused using a single-pass technique, and phenol red was momentarily introduced to this system from the portal side. Outflow dilution patterns of phenol red were analyzed using statistical moment theory, and kinetic parameters of hepatic distribution and elimination of phenol red were calculated from moments, namely, the hepatic extraction ratio (Ei) and elimination rate constant (kel,i). A larger distribution volume (Vi) was obtained for phenol red than for 131I-human serum albumin (HSA) and 51Cr-red blood cells (RBC), indicating its extravascular diffusivity. The biliary excretion of conjugated phenol red was delayed relative to that of the free agent. The larger biliary mean transit time (tbile,conj.) represents the processes of biliary transport and intrahepatic metabolism. Further, the effects of dose and perfusion temperature on the hepatobiliary transport of phenol red were determined. With high doses or low perfusion temperatures (20 and 27 degrees C), Ei, kel,i, and intrinsic clearance (CLint,i) of phenol red and biliary recovery of free and conjugated phenol red (Fbile,free, Fbile,conj) significantly decreased. The temperature-dependent and saturable processes in hepatic uptake, metabolism, and biliary excretion of phenol red were assessable to moment analysis.

Animals↗
PubMed1989

Analysis of drug penetration through the skin by the two-layer skin model.

A diffusion model for the skin penetration of drug in the finite-dose system was developed considering the skin to be composed of two layers, the outermost layer (stratum corneum) and the lower layer (viable epidermis and dermis). Based on this skin model, the Laplace transforms of the equations for the drug amounts in the receptor, the vehicle, and the skin were derived. The penetration profiles of 6-mercaptopurine (6-MP) through the intact and stripped guinea pig skin were obtained from in vitro diffusion experiments. The computer fitting of those profiles to the Laplace-transformed equations by a nonlinear least-squares program based on a fast inverse Laplace transform algorithm [MULTI-(FILT)] gave parameters such as diffusion coefficients of 6-MP and thicknesses of both layers. The mean transit time (MTT) for each diffusion process was defined based on statistical moment concept and calculated using the obtained parameters. Under the present condition, the process to move from the vehicle to the stratum corneum is demonstrated to have the longest mean time in overall processes of 6-MP penetration.

Animals↗
PubMed1989

Sagittal tomography in the supine patient.

The authors have developed a multidirectional tomographic unit to obtain sagittal images with the patient in the supine or prone position. The apparatus is particularly useful for examination of the vertebral column and sella turcica. It can be employed in circular (0 degrees -40 degrees) and spiral (10 degrees -32 degrees) motions. The apparatus provides correct and easy positioning of subjects with easy maintenance of posture. It reduces the distortional effects of respiration and thereby markedly improves reproducibility.

Humans↗
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↗