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Biomedical subjects

S Muranishi

Publications and source records attributed to S Muranishi.

At least 19 recordsLinked to original sources
PubMed1992

Further mechanistic study on intestinal absorption enhanced by unsaturated fatty acids: reversible effect by sulfhydryl modification.

In order to study the relationship between the sulfhydryl (SH) modification of membrane-associated proteins and the oleic acid-induced permeability enhancement of the colonic mucosa, in vitro and in situ absorption studies were performed using rat colon and carboxyfluorescein as an impermeable dye. The pretreatment of the mucosa with diamide, a bifunctional sulfhydryl modifier, in in vitro experiments with the everted colonic loops reduced the absorption enhancing effect of oleic acid in a concentration-dependent manner, less inhibitory effect, though just a little, was observed as compared to N-ethylmaleimide. The inhibition caused by the addition of diamide was absolutely restored by exposure of the mucosa to dithiothreitol. On the other hand, these SH modifiers showed no pronounced effect on the in vivo permeability of quinine which is well-known to be absorbed by a passive transport system mainly via the membrane lipid bilayer. These results obtained in the present study have identified an important role of the functional SH groups of membrane proteins on modulating the permeability alteration of the mucosal epithelium provoked by oleic acid. Furthermore, the SH proteins have been revealed as being unimportant in the intestinal absorption of lipoid-soluble compounds.

Animals↗
PubMed1992

Molecular weight-dependent lymphatic transfer of exogenous macromolecules from large intestine of renal insufficiency rats.

To study the lymphatic delivery of exogenous macromolecules via the enteral route in renal insufficiency, we determined the transfer selectivity to the systemic blood and lymph of fluorescein isothiocyanate-labeled dextrans of different average molecular weight (10, 18, 39, and 69kD). The compounds were administered into the large intestinal lumen of rats with occluded renal circulation, with the aid of lipid-surfactant mixed micelles as an absorption prometer. Whereas concentrations of the smaller dextrans (molecular weight under 18 kD) in the lymph of the thoracic duct and in the peripheral plasma were similar, levels of dextrans over 39 kD were significantly higher in the lymph than in the plasma. Further, dextran plasma concentrations decreased in inverse proportion to increasing molecular weight. The molecular weight threshold for a high lymph-to-blood level ratio (18-39 kD) was higher than that previously found in rats with normal renal function (10-18 kD). This difference was accounted for by reduced renal clearance of the low molecular weight dextrans in renal failure. These results are useful in the design of lymphotropic drug delivery in disease states.

Animals↗
PubMed1992

Toxicity of a new dosage format, cisplatin incorporated in lactic acid oligomer microspheres, in mice.

A new drug delivery system, cisplatin incorporated into lactic acid oligomer microspheres (CDDP-MS), was developed for the treatment of peritoneal carcinomatoses. We studied the acute toxicity and pathological effects of CDDP-MS injected intraperitoneally in mice. The 50% lethal dose was 23.8 mg/kg (21.3-26.7 mg/kg at 95% level of confidence), which was 1.76 times that of the cisplatin aqueous solution of 13.5 mg/kg (11.9-15.3 mg/kg at 95% level of confidence). The duration for the restoration of the body weight loss was prolonged when CDDP-MS at doses close to the 50% lethal dose was administered, as compared with the cisplatin aqueous solution at doses close to its 50% lethal dose. On autopsy there were no macroscopic or microscopic differences between the two dosage forms.

Animals↗
PubMed1992

Improvement of large intestinal absorption of insulin by chemical modification with palmitic acid in rats.

The intestinal absorption of 125I-labelled palmitoyl insulin was examined following administration into in-situ closed large intestinal loops of rats. When mono- and dipalmitoyl insulins (Palins-1 and Palins-2, respectively) were administered in polyoxyethylene hydrogenated castor oil (HCO 60) micellar system into intestinal loops, a marked increase in plasma radioactivity and a corresponding disappearance of residual radioactivity in the intestinal lumen were observed in the following rank order: Palins-2 greater than Palins-1 greater than native insulin. In addition, the derivatives were more stable than native insulin in the mucosal tissue homogenates of the large intestine. These results suggest that chemical modification of insulin with palmitic acid may not only increase the lipophilicity of insulin but also reduce its degradation, resulting in the increased transfer of insulin across the large intestinal mucous membrane. The linoleic acid-HCO 60 mixed micelles system did not have a significant effect on the large intestinal absorption of radioactivity associated with the lipophilic insulin analogues.

Animals↗
PubMed1992

Improvement of intestinal absorption of thyrotropin-releasing hormone by chemical modification with lauric acid.

Intestinal absorption of 125I-labelled lauryl thyrotropin-releasing hormone (Lau-TRH), a novel lipophilic derivative of TRH, was examined by rat in-situ closed intestinal loops. At a dose of 1 mumol per rat into the small intestine, a significant increase in percent of dose in plasma radioactivity of Lau-TRH was observed in comparison with that of TRH. A dose-dependent decrease in percent of dose in plasma radioactivity of TRH was noted, suggesting a saturable process of TRH transport. In contrast, the percent of dose in plasma radioactivity of Lau-TRH increased with increasing dose of Lau-TRH. The stability of TRH and Lau-TRH was studied in plasma and rat small intestinal homogenates. Lau-TRH was more stable than TRH in rat plasma. These results suggest that chemical modification of TRH with lauric acid may not only increase the lipophilicity of TRH but also reduce the degradation of TRH, resulting in the increased plasma radioactivity of TRH. On the other hand, Lau-TRH was gradually converted to TRH in the intestinal mucosal homogenate. These findings indicate that chemical modification of TRH with lauric acid might be a useful approach for improving the intestinal absorption of this peptide.

Animals↗
PubMed1992

Etoposide microcrystals suspended in oil: a new dosage form to peritoneal carcinomatosis in mice.

Etoposide microcrystals suspended in oil (ETOP-OIL) were examined for their therapeutic effects on peritoneal carcinomatosis in mice. Two days after intraperitoneal inoculation with 10(5) P388 leukemia cells/mouse to CDF1 male mice, etoposide at 10-80 mg/kg was administered intraperitoneally in bolus in the form of ETOP-OIL or in the aqueous solution form. In every dose, the survival curve of the mice given ETOP-OIL was statistically significantly improved in spite of its small lethal toxicity, as compared with those given the identical dose of etoposide aqueous solution.

Animals↗
PubMed1992

Transfer of exogenous macromolecules from rat stomach wall to blood and lymph is dependent on molecular weight.

Transfer selectivity to the blood and the lymph of exogenous dextrans of various average molecular weight (approximate 4, 10, 18, 39 and 70 kilodaltons (kDa)) after dosing to the subserosal layer of the rat stomach wall was investigated by measuring the fluorescein isothiocyanate labelled dextran concentrations in the lymph of the thoracic duct and the peripheral plasma. The lymph/plasma level ratio of the dextrans rose greatly with the increase in molecular weight (over 10kDa) owing largely to the lower plasma concentration, although the lymph levels of small dextran (4kDa) were not significantly higher than the plasma levels. These results indicate that there is an inverse relation between plasma levels of dextrans and their molecular weight, and also suggest that the molecular weight threshold of transfer selectivity of dextran to the blood and the lymph administered in the rat stomach wall is between 4-10 kDa.

Animals↗
PubMed1992

Enhanced therapeutic efficacy of intralymph-nodal etoposide on distal lymph node metastases using a new dosage format--activated carbon particles adsorbing etoposide.

Small activated carbon particles adsorbing etoposide were injected into the proximal lymph nodes of mice and tested for therapeutic effect on distal lymph node metastases. Eight days after s.c. inoculation of 5 x 10(5) P388 leukemia cells in the left hind foot pad of mice, when metastases had been established in the secondary draining lymph nodes (lower paraaortic nodes), etoposide (5 mg/kg) was injected into the primary draining node (left popliteal node) in the form of activated carbon particles adsorbing etoposide (ETOP-CH group) or etoposide aqueous solution. After drug administration, the primary lesion was removed so that lymph node metastases were not affected by the primary lesion. Two days after drug administration, the secondary draining nodes were extirpated, and the P388 leukemia cell number in these nodes was estimated by an i.p. transference method. The estimated number of P388 leukemia cells in the lymph nodes in the ETOP-CH group was statistically significantly (by Student's t-test, P less than 0.05-0.005) less than the number of P388 leukemia cells in the other treatment groups.

Animals↗
PubMed1991

Lipophilic peptides: synthesis of lauroyl thyrotropin-releasing hormone and its biological activity.

Thyrotropin-releasing hormone (TRH) was derivatized by chemical attachment of lauric acid to the N-terminal pyroglutamyl group. The product was confirmed to be more lipophilic than TRH by high-performance liquid chromatography and measurement of partition coefficients. The central nervous system activity and endocrine activity of the lauroyl derivative were only slightly reduced, to 81 and 64% of the parent TRH, respectively. Lipophilic derivatization may be generally applicable to transmembrane delivery of peptides.

Amino Acid Sequence↗
PubMed1991

Selective distribution of aclarubicin to regional lymph nodes with a new dosage form: aclarubicin adsorbed on activated carbon particles.

A new dosage form (ACR-CH) comprising aclarubicin adsorbed on activated carbon particles was designed to sustain release of aclarubicin. ACR-CH or aclarubicin aqueous solution (ACR-sol) was injected subcutaneously into the fore foot-pads of rats. ACR-CH distributed a statistically significantly higher level of aclarubicin to the axillary lymph nodes (detectable up to 7 days after injection) than aclarubicin distributed in an ACR-sol (not detectable after 48 h). To other tissues, ACR-CH distributed statistically significantly low levels of aclarubicin, as compared with ACR-sol.

Aclarubicin↗
PubMed1991

A new dosage form comprising a suspension of activated carbon particles adsorbing aclarubicin: toxicity in mice.

A new dosage form (ACR-CH), a suspension of small activated carbon particles adsorbing aclarubicin, was studied for its toxicity and histopathological effects on organs in mice. The 50% lethal subcutaneous dose of ACR-CH was 83.5 mg/kg, a value 2.42 times that (34.5 mg/kg) of the aclarubicin aqueous solution. The duration of the toxic effects of ACR-CH was prolonged compared with that of the aclarubicin aqueous solution. On autopsy there was no remarkable difference in macroscopic and microscopic examinations between the two dosage forms.

Aclarubicin↗
PubMed1991

Pharmacokinetics of FK-506, a novel immunosuppressant, after intravenous and oral administrations to rats.

A pharmacokinetic study of FK-506 (FK), a novel immunosuppressant being about hundred times more potent than cyclosporin A (CyA) in the in vitro experiment, has been performed in rats after intravenous and oral administrations at two doses, 1.0 and 5.0 mg/kg. As compared with CyA, plasma, bile, urine and lymph FK levels were determined by a fluorescence high-performance liquid chromatographic method with chemiluminescence detection. Non-compartment pharmacokinetic parameters were calculated by area/moment analysis. After the i.v. injection of FK at 1.0 and 5.0 mg/kg, the total plasma clearance, CLtot, was 7.028 +/- 0.076 (mean +/- S.E.) and 7.651 +/- 0.755 ml/min, steady-state distribution volume, Vd.ss, was 4623 +/- 28 and 4201 +/- 529 ml/kg, elimination half-life at the terminal elimination phase, t1/2 beta, was 2.36 +/- 0.25 and 2.54 +/- 0.29 h, and the volume of the initial distribution space, V1, was 1336 +/- 150 and 1065 +/- 115 ml/kg, respectively. By comparing the pharmacokinetic parameter with CyA, the CLtot of FK is about three times greater than that of CyA. There is not a significant difference on t1/2 beta between CyA and FK. The V1 and Vd.ss of FK are 4-5 times greater than that of CyA. Therefore, higher clearance of FK is ascribed not only to the faster elimination from the rat body but also to the greater distribution space in the body. The mean percentage of FK transferred into the thoracic lymphatics over 6 h were 0.09 +/- 0.02% (1.0 mg/kg) and 0.16 +/- 0.02% (5.0 mg/kg), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1991

[Adsorption and desorption of aclarubicin into and from activated carbon particles as drug carrier--an in vitro study].

A new dosage form (ACR-CH), aclarubicin(ACR) adsorbed on activated carbon particles (CH), was studied for adsorption and desorption onto and from CH. The adsorption isotherm at 37 degrees C in saline and phosphate buffer (pH 7.4-7.5) were shown as M = 175 Co.15 and M = 207 Co.24, respectively (M = ACR amount adsorbed on CH, microgram/mg; C = ACR concentration in a free state, microgram/ml). In both fluids, CH adsorbed more than 100-1,000 times more amount of ACR than ACR in a free state. ACR-CH was lavaged 7 times and the released ACR in a free state was measured. The results showed that ACR-CH desorbed constantly a small amount of ACR, namely, 1.5-8 percent of initial concentration of ACR in a free state in saline, 0.1-10% in phosphate buffer, and 0.5-4.0% in Ringer's solution. Under the same conditions, desorption of ACR-CH was measured in dog's blood plasma. The first lavage made ACR-CH desorb at 25.7 +/- 0.85 percent of ACR initial concentration in a free state, and two times' to 7 times' lavage made 1-3%. Overall, 43.3 +/- 0.99% of ACR were desorbed from the activated carbon. It was concluded that ACR-CH slowly released a constant amount of ACR for a long period.

Aclarubicin↗
PubMed1990

Combinative improving effect of increased solubility and the use of absorption enhancers on the rectal absorption of uracil in beagle dogs.

An improvement of the rectal absorption of uracil was examined by the application of absorption enhancers in addition to the increased solubility of uracil. Uracil was ground with additives such as MgO, sodium 2,6-dihydroxybenzoate, human serum albumin or hydroxypropylmethylcellulose acetate succinate. Aqueous, oily and powdery formulations, which consisted of the ground mixtures, nicotinamide, urea and absorption enhancers such as polyoxyethylene (23) cetylether (BC-23) or sodium caprate, were prepared. Uracil solubility in the aqueous formulations was increased about 4-13 times that in the corresponding control formulations. When rectally administered to beagle dogs, marked increases in the plasma uracil level were observed in some of the cases of aqueous and oily formulations. In the powdery formulations and formulations containing macromolecular additives, however, absorption improvements was not observed. The results indicated that an improvement in the absorption of uracil was caused by the combinative improving effect of the increased uracil solubility and the promoting effect of absorption enhancers.

Absorption↗
PubMed1990

Absorption enhancers.

Many current therapeutic drugs, e.g., antibiotics and peptide drugs, are impermeable to outer tissue barriers. Drug delivery of impermeable drugs through such barriers is currently one of the major interests in pharmaceutical research. New classes of absorption enhancers provide rapid absorption in the gastrointestinal tract or skin, with no side effects. This review covers the history of enhancer research, an overview of a variety of absorption enhancers, the nature of enhancing action, and site specificity. The final section focuses on the mechanisms of enhancer action which transiently abolishes or reverses barrier resistance, from the viewpoints of the lipid bilayer barrier containing SH proteins, as well as transcellular/paracellular pathways. Fully understanding these mechanisms is of importance for therapeutic applications.

Adjuvants, Pharmaceutic↗
PubMed1989

Synthesis of palmitoyl derivatives of insulin and their biological activities.

In order to improve the lipophilicity of peptides, bovine insulin was chosen for the chemical modification using palmitic acid. The N-hydroxysuccinimide ester of palmitic acid was used for attachment to terminal amino groups, and p-methoxybenzoxycarbonyl azide was used for protection of the glycine-A1 amino terminus. We obtained two purified derivatives of insulin, B1-monopalmitoyl- and B1,B29-dipalmitoyl-insulin, which were confirmed to be more lipophilic than the parent insulin on high-performance liquid chromatography (HPLC). The hypoglycemic effects of both products were measured in rats after intravenous and intramuscular injections. The mono derivative was more active than the di derivative and produced a longer effect duration than the native insulin after intravenous injection. The derivatives were also shown to be less immunoreactive as judged by an enzyme immunoassay.

Amino Acids↗