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S Muranishi

Publications and source records attributed to S Muranishi.

At least 37 records · Page 2Linked to original sources
PubMed1997

Improvement of the pulmonary absorption of (Asu1,7)-eel calcitonin by various absorption enhancers and their pulmonary toxicity in rats.

The effects of absorption enhancers on the pulmonary absorption of (Asu1,7)-eel calcitonin (ECT) and their pulmonary toxicity were examined by means of in situ pulmonary experiments. The absorption of ECT from the lungs was estimated by its hypocalcemic effect. The pulmonary membrane toxicity of absorption enhancers was evaluated by the leakage of Evans Blue from the plasma into the lungs. In the absence of absorption enhancers, a slight hypocalcemic effect was obtained following intrapulmonary administration of ECT. However, we found significant hypocalcemic effects after the ECT administration with 10 mM n-lauryl beta-D-maltopyranoside (LM), 10 mM sodium glycocholate (NaGC), and 10 mM linoleic acid-HCO60 (hydrogenated caster oil) mixed micelle (MM). The plasma calcium levels decreased as the amount of LM coadministered with ECT increased. In contrast, 10 mM EDTA did not improve the pulmonary absorption of ECT. Overall, a correlation between the pulmonary absorption of ECT and local toxicity was observed in the presence of these additives. However, 1 mM LM, 10 mM NaGC, and 10 mM MM improve the pulmonary absorption of ECT with low pulmonary toxicity. These findings suggest that the use of these adjuvants would be a useful approach for improving the pulmonary absorption of ECT.

Absorption↗
PubMed1997

Chitosan capsules for colon-specific drug delivery: improvement of insulin absorption from the rat colon.

The objective of this study was to estimate colon-specific insulin delivery with chitosan capsules. In vitro drug release experiments from chitosan capsules containing 5(6)-carboxyfluorescein (CF) were carried out by the Japan Pharmacopoeia (J. P.) rotating basket method with some slight modifications. The intestinal absorption of insulin was evaluated by measuring the plasma insulin levels and its hypoglycemic effects after oral administration of the chitosan capsules containing insulin and additives. Little release of CF from the capsules was observed in liquid 1, an artificial gastric juice (pH 1), or in liquid 2, an artificial intestinal juice (pH 7). However, the release of CF was markedly increased in the presence of rat cecal contents. A marked absorption of insulin and a corresponding decrease in plasma glucose levels was observed following the oral administration of these capsules that contain 20 IU of insulin and sodium glycocholate (PA% = 3.49%), as compared with the capsules containing only lactose or only 20 IU of insulin (PA% = 1.62%). The hypoglycemic effect started from 8 h after the administration of chitosan capsules when the capsules entered the colon, as evaluated by the transit time experiments with chitosan capsules. These findings suggest that chitosan capsules may be useful carriers for the colon-specific delivery of peptides including insulin.

Animals↗
PubMed1997

Metabolism of azetirelin, a new thyrotropin-releasing hormone (TRH) analogue, by intestinal microorganisms.

PURPOSE: We evaluated the effect of luminal bacterial metabolism on intestinal absorption of azetirelin in rats. In vitro characteristics of bacterial metabolism of azetirelin were also investigated with the goal of overcoming the low stability of the peptidic drug against luminal microorganisms. METHODS: Plasma azetirelin levels after oral administration to antibiotic-pretreated rats was examined. In vitro incubation experiments with bacterial suspensions were also performed to clarify the location of azetirelin breakdown activity as well as the effects of oxygen, pH, and various protease inhibitors on drug metabolism. RESULTS: Plasma azetirelin levels were sustained after oral administration to antibiotic-treated rats. Incubation with rat luminal contents demonstrated that azetirelin was metabolized by anacrobic bacteria, which are predominant in the distal intestine. Fecal suspensions from rats, dogs, and humans showed comparable metabolic activity. Azetirelin breakdown in the bacterial suspension was pH-dependent and was inhibited in the presence of bacitracin or puromycin. CONCLUSIONS: Bacterial metabolism influences the degree of absorption of azetirelin in the distal intestine. Control of the luminal pH environment may be a practical method for improving the stability of azetirelin against intestinal microorganisms.

Animals↗
PubMed1997

Selective delivery of 5-fluorouracil (5-FU) to i.p. tissues using 5-FU microspheres in rats.

A new formulation has been developed for the delivery of 5-fluorouracil (5-FU) in treating peritoneal carcinomatosis. The new formulation (5-FU-MS) involves the incorporation of 5-FU into microspheres composed of a poly(glycolide-co-lactide) matrix. The incorporated 5-FU is released slowly over a 3 week period. We investigated the drug distribution and pharmacokinetics of 5-FU in rats receiving an i.p. injection of 5-FU-MS or aqueous 5-FU solution. The concentration of 5-FU was higher in the i.p. tissues (omentum and mesentery) and lower in the extraperitoneal tissues (blood plasma, lung and heart) in rats given 5-FU-MS than in rats given the aqueous 5-FU solution. Pharmacokinetic analysis showed that the area under the curve (AUC) was significantly greater in the omentum and the mesentery than in other tissues of rats given 5-FU-MS. There was no significant difference in the AUC in the tissues of rats given the aqueous 5-FU solution.

Animals↗
PubMed1997

Effects of different absorption enhancers on the permeation of ebiratide, an ACTH analogue, across intestinal membranes.

The permeation of ebiratide (H-Met(O2)-Glu-His-Phe-D-Lys-Phe-NH(CH2)8NH2), a novel ACTH analogue, across the intestinal mucosae has been examined by use of isolated intestinal membranes from rats in a modified Ussing chamber. Regional differences were observed in the permeation of ebiratide across intestinal membranes; the order of membrane permeability was jejunum > ileum > duodenum > colon. Overall, the permeation of ebiratide was relatively poor. The effects of various absorption enhancers were examined to increase the intestinal permeability to ebiratide. Sodium glycocholate and sodium caprate had no significant enhancing effect on the permeability of the jejunal membrane, but significantly enhanced the permeation of ebiratide through the colonic membrane. On the other hand, N-dodecyl-beta-D-maltopyramoside (LM) significantly enhanced the permeation of ebiratide through both jejunal and colonic membranes. In general, the absorption-enhancing effects of these agents were more predominant in the colon than in the jejunum. Membrane damage by the absorption enhancers was evaluated by measuring the amount of protein released from the intestinal membrane. It was found that all the absorption enhancers slightly increased the amount of protein released, but that the amounts of protein released in the presence of these enhancers were much less than in the presence of ethylenediaminetetraacetic acid (EDTA), used as a positive control. These findings suggest that the absorption enhancers, especially LM might be useful adjuvants for improving the intestinal absorption of peptide and protein drugs, including ebiratide.

Adrenocorticotropic Hormone↗
PubMed1997

Degradation of insulin and calcitonin and their protection by various protease inhibitors in rat caecal contents: implications in peptide delivery to the colon.

The objective of this study was to examine the metabolism of insulin and calcitonin, and their protection by various protease inhibitors, in the large intestine. Fresh caecal contents were prepared from non-fasted rats and the degradation of insulin and calcitonin was studied in a suspension of rat caecal contents, as a model of the content of the large intestine. Both insulin and calcitonin were metabolized in suspensions of rat caecal contents, but the degradation of calcitonin was much faster than that of insulin. The degradation of insulin was fastest at pH 6.8. Protease inhibitors such as camostat and aprotinin inhibited the degradation of insulin and calcitonin in rat caecal contents, which was consistent with the high chymotrypsin activity of these contents. These findings suggest that care should be taken when administering peptide drugs to the large intestine for colon-specific drug delivery because they can be degraded in rat caecal contents. Protease inhibitors might be useful for increasing the stability of these peptides in the large intestine, thereby improving their large-intestinal absorption to the systemic circulation.

Animals↗
PubMed1997

Effects of various absorption enhancers on the intestinal absorption of water soluble drugs by in vitro Ussing chamber method: correlation with an in situ absorption experiment.

The effect of absorption enhancers on the small and large intestinal absorption of drug in rats was examined using an in vitro modified Ussing chamber method, and the results were compared with those from an in situ absorption experiment. Phenol red was chosen as a model drug, while the absorption enhancers used were sodium glycocholate (Na-GC), sodium taurocholate (Na-TC), sodium deoxycholate (Na-DC), EDTA, sodium salicylate (Na-Sal), sodium caprate (Na-Cap), diethyl maleate (DEM) and N-lauryl-beta-D-maltopyranoside (LM), all used at a concentration of 20 mM. This modified Ussing chamber method showed that Na-DC, EDTA and LM were the most effective absorption enhancers in the large intestine. A good correlation exists between the area under the curve (AUC) (in situ loop model) and the cumulative amount of phenol red absorbed (in vitro modified Ussing chamber method). These results indicated that the in vitro modified Ussing chamber method can be used to evaluate the effects of various absorption enhancers in the intestine.

Animals↗
PubMed1997

[Delivery system design for improvement of intestinal absorption of peptide drugs].

Most people drugs are hydrophilic molecules with a molecular weight between 300 and 20,000 and such molecules are usually given by parenteral administration. In many cases, enteral administration of these peptides via the gastrointestinal tract is preferred. However, oral administration of peptides and proteins is often limited by their instability in the gastrointestinal environment and/or poor absorption from the gut. To promote the absorption of these drugs, we first discovered unsaturated fatty acids with absorption enhancing activities and less harmful properties to the gastrointestinal membranes in hydrolysates of natural oil. The mechanisms whereby the permeability of drugs was enhanced by the fatty acids are associated with the disorder in the membrane's interior and the interaction of these fatty acids with the polar head group of phospholipid. Furthermore, we suggested that a SH-related substance was involved in the permeability enhancing effect of these fatty acids. Secondly, we developed a lympho-targeting delivery system for bleomycin by the combined effects of an ion-pair complex with dextran sulfate (DS) and an absorption enhancer. We found a very high lymphatic concentration when administered bleomycin-DS together with the absorption enhancer. Its mechanism may be due to a molecular sieving in the blood-lymph barrier in the intestinal tissues. Finally, to improve the intestinal absorption of peptides, we synthesized novel lipophilic derivatives of peptides including TRH (thyrotropin releasing hormone), tetragastrin, enkephalin, calcitonin and insulin by a chemical modification with fatty acids, while maintaining their pharmacological activities. The stability and permeability of these peptides were improved by acylation with some fatty acids having appropriate carbon numbers. Thus, we have established the strategies for improving the delivery of peptide drugs by various approaches. In future, the combination use of these approaches will be expected to develop the delivery systems of these drugs for therapeutic treatment.

Acylation↗
PubMed1997

Pharmacokinetics of mitomycin C (MMC) after intraperitoneal administration of MMC-gelatin gel and its anti-tumor effects against sarcoma-180 bearing mice.

Gelatin viscous solution containing mitomycin C (MMC) was prepared and its antitumor effects were evaluated toward sarcoma-180 (S-180) ascite tumor bearing mice. Among various gelatin concentrations, 3% and 5% gelatin solutions potentiated the antitumor effects of MMC (7.5 mg/kg) against S-180 bearing mice. A "bell-shaped" profile was observed between % release of MMC from the gelatin matrix and increased life span (ILS) %. On the other hand, in the case of 10 mg/kg dose of MMC, 7.5% and 10% gelatin solutions potentiated its antitumor effects. At both doses of 7.5 and 10 mg/kg of MMC, decrease in body weight of mice after intraperitoneal administration of MMC were suppressed by increasing the concentration of gelatin. To confirm a possible mechanism for increase in ILS % after intraperitoneal (i.p.) administration of the gelatin viscous solution containing MMC, we examined the pharmacokinetics of MMC after i.p. administration into rats. By the use of 3 % gelatin solution, mean residence time (MRT) and Tmax values were significantly prolonged, and Cmax was decreased as compared with the administration of MMC solution. These results suggested that the enhancement of antitumor effect of MMC by the gelatin viscous solution could be caused by decrease in the clearance rate of MMC from the peritoneal cavity to systemic circulation due to decreasing its diffusivity in gelatin matrix.

Animals↗
PubMed1996

Methotrexate bound to carbon particles used for treating cancers with lymph node metastases in animal experiments and a clinical pilot study.

BACKGROUND: A new dosage formulation, methotrexate adsorbed onto activated carbon particles (MTX-CH), was developed for treating cancer patients with lymph node metastases. METHODS: MTX-CH injected subcutaneously into the left hind foot pad of rats delivered greater amounts of methotrexate selectively to the regional lymph nodes and to the injection site for longer periods than did the same dose of methotrexate in aqueous solution. Seven days after mice received a subcutaneous inoculation with 5 x 10(5) P388 leukemia cells in the left hind foot pad, when metastasis had occurred in the left popliteal lymph node, methotrexate was injected subcutaneously into the left hind foot pad in the form of either MTX-CH or methotrexate aqueous solution. In clinical trials, patients with cancers in relatively early stages (5 patients with gastric cancer and 1 with esophageal cancer) each received local injections of MTX-CH doses of 250 to 500 mg under fiberscope. RESULTS: MTX-CH extended the survival time better than did methotrexate aqueous solution. In mice who received an inoculation of P388 leukemia cells and drug treatment using the same procedures, the treatment effects on metastases to the regional lymph nodes were significantly greater in mice treated with the MTX-CH than in those given methotrexate aqueous solution. MTX-CH controlled the disease well for 25 to 35 months. CONCLUSIONS: Local injection of MTX-CH is apparently useful for treating digestive cancers with lymph node metastases in patients who have difficulty tolerating surgery.

Aged↗
PubMed1996

Enhancement of intestinal transport of thyrotropin-releasing hormone via a carrier-mediated transport system by chemical modification with lauric acid.

The transport characteristics of thyrotropin-releasing hormone (TRH) and its chemically modified derivative with lauric acid (Lau-TRH) across the rat small or large intestine were estimated by means of an in vitro everted sac experiment. Both compounds were especially absorbed from the upper small intestine. The penetration of TRH across the upper small intestine was significantly increased by conjugation with lauric acid. Lau-TRH administered to the mucosal side appeared as a native TRH form in the serosal side. On the other hand, a temperature dependency and a directional difference in the transfer rates of these compounds were observed in the everted and non-everted sacs of the upper small intestine. Moreover, the penetration of TRH and Lau-TRH across the upper small intestine was inhibited by 0.25 mM 2,4-dinitrophenol and 10 mM glycylglycine. In addition, Lau-TRH was very stable in the cytosolic fraction of the small intestinal mucosa, while it was gradually converted to the native TRH in the brush-border membrane (BBM) fraction. The binding amounts of TRH to the BBM were remarkably enhanced by the lauric acid conjugation; however, its binding was nonspecific. Therefore, it was suggested that Lau-TRH rapidly bound to the BBM in the small intestine, where Lau-TRH is converted to TRH, and this released TRH is efficiently transported by an oligopeptide transporter which exists in the upper small intestine.

2,4-Dinitrophenol↗
PubMed1996

Effects of protease inhibitors on the absorption of phenol red and fluorescein isothiocyanate dextrans from the rat intestine.

The absorption enhancement effects of three types of protease inhibitors, aprotinin, bacitracin, and soybean trypsin inhibitor, on the small and large intestinal absorption of phenol red (PR) and fluorescein isothiocyanate dextrans (FDs) were examined in rats. Of these protease inhibitors, only bacitracin enhanced the absorption of PR and FDs from the rat small and large intestine. Thus, we suggest that bacitracin has not only a protease-inhibitory but also an absorption-enhancing capability. We examined the effects of various protease inhibitors on intestinal mucosal toxicity by measuring the leakage of Evans blue (EB) from the systemic circulation. Although there was a significant increase in the leakage of EB in the presence of bacitracin, it was considerably less than that in the case of polyoxyethylene 9-lauryl ether (BL-9), which was used as a positive control. Therefore, bacitracin may be a good model adjuvant for improving the intestinal absorption of poorly absorbable drugs because it did not cause serious intestinal mucosal damage, as seen in the case of BL-9.

Animals↗
PubMed1996

Transport of drugs across the Xenopus pulmonary membrane and their absorption enhancement by various absorption enhancers.

PURPOSE: The permeability of drugs across the Xenopus pulmonary membrane and the effects of various absorption enhancers on their absorption were examined using an in vitro Ussing chamber technique. METHODS: Phenol red and fluorescein isothiocyanate-labeled dextrans (FDs) with different molecular weights were chosen as water-soluble model drugs. Absorption enhancers used in this study were N-lauryl-beta-D-maltopyranoside (LM), linoleic acid-HC060 mixed micelle (MM), sodium glycocholate (Na-GC), sodium caprate (Na-Cap), sodium salicylate (Na-Sal) and disodium EDTA (EDTA). RESULTS: The permeability of drugs gradually decreased with increasing their molecular weights, and the absorption of phenol red significantly increased by these absorption enhancers. Among these additives, LM, MM and Na-Cap appeared to be more effective for enhancing the permeability of drugs than the others. Furthermore, we plotted the logarithm of apparent permeability coefficient (Papp) of these drugs against the logarithm of their molecular weights. There exists a good correlation between these parameters. We measured transmembrane resistance(Rm) of Xenopus pulmonary membrane during the transport experiment to examine the membrane integrity. The average Rm value was about 700 omega.cm2, and this value was maintained for 3 hr. CONCLUSIONS: This method is useful for estimating the transport characteristics of drugs across the pulmonary membrane.

Absorption↗
PubMed1996

Pharmacological effects of 5-fluorouracil microspheres on peritoneal carcinomatosis in animals.

A new delivery formulation (5FU-MS) of 5-fluorouracil (5FU), 5FU incorporated in microspheres composed of poly(glycolide-co-lactide) matrix, has been developed for the treatment of peritoneal carcinomatosis, and is designed to slowly release the incorporated 5FU for 3 weeks. Intraperitoneal 5FU-MS distributed higher concentrations of 5FU to the intraperitoneal tissues, such as the omentum and the mesentery, for a longer period with lower blood plasma concentrations than did the aqueous 5FU solution in rats. In experiments using mice, the lethal toxicity, determined by the probit method, in 5FU-MS was reduced to less than half that in aqueous 5FU solution. We evaluated the therapeutic effects on peritoneal carcinomatosis induced by the intraperitoneal inoculation of B-16 PC melanoma cells. The therapeutic effects of 5FU-MS were enhanced when compared with both the equivalent doses and same toxicity doses of the aqueous 5FU solution.

Animals↗
PubMed1996

New formulation of 5-fluorouracil in microspheres reduces toxicity in mice.

A new dosage formulation of 5-fluorouracil incorporated in microspheres (5-FU-MS) was developed for the treatment of peritoneal carcinomatosis. We studied the acute toxicity and side effects of i.p. 5-FU-MS in mice. The 50% lethal dose value for 5-FU-MS was 535.4 mg/kg of 5-FU, which was 2.22 times that of the aqueous 5-FU solution. Deaths occurred 12-17 days after the administration of 5-FU-MS, but within 11 days after the administration of aqueous 5-FU. Thus, lethal toxicity appeared later with 5-FU-MS than with aqueous 5-FU. There were no differences in pathologic findings on autopsy between mice given the two dosage formulations.

Animals↗
PubMed1996

Effectiveness and toxicity screening of various absorption enhancers in the rat small intestine: effects of absorption enhancers on the intestinal absorption of phenol red and the release of protein and phospholipids from the intestinal membrane.

Sodium glycocholate, sodium taurocholate, sodium deoxycholate, EDTA, sodium salicylate, sodium caprate, diethyl maleate, N-lauryl-beta-D-maltopyranoside, linoleic acid polyoxyethylated (60 mol) mixed micelles (all 20 mM) have been ranked in order of their effectiveness as enhancers of the absorption of drugs in the rat small intestine, by use of an in-situ loop model with phenol red as a model drug. Local toxicity in rats was examined by assessing protein and phospholipid release as biological markers. Of the absorption enhancers, sodium deoxycholate, EDTA and N-lauryl-beta-D-maltopyranoside were the most effective; sodium deoxycholate and EDTA, however, caused significant release of protein and phospholipids. N-lauryl-beta-D-maltopyranoside, on the other hand, did not damage the small intestinal membrane. Sodium taurocholate enhanced phenol red absorption from the small intestine and resulted in little or no protein and phospholipids release. Sodium salicylate, diethyl maleate and the mixed micelles had no absorption-promoting effects on phenol red. There was good correlation between the area under the plasma concentration-time curve for phenol red and the amounts of protein and phospholipid released in the presence of absorption enhancers. From these results it might be concluded that N-lauryl-beta-D-maltopyranoside and sodium taurocholate are effective absorption enhancers which have low toxicity levels at a concentration of 20 mM.

Animals↗