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K Tadano

Publications and source records attributed to K Tadano.

At least 37 records · Page 2Linked to original sources
PubMed1995

Distribution of menaquinone-4, a therapeutic agent for osteoporosis, in bone and other tissues of rats.

[14C]Menaquinone-4 was administered orally once daily at a dose of 4 mg/kg for ten days to female rats of different ages to determine its blood and tissue distribution with particular attention to its distribution in bone. Animals aged 10 and 30 months were either ovariectomized or sham-operated as a control, and young rats aged 7 weeks were used as untreated controls. Blood concentrations of radioactivity at 24h after each dose during repeated administration increased daily and approached a steady rate by the seventh dose. Higher concentrations of radioactivity in blood (plasma) were observed in older animals than in the younger ones, but there was little difference between ovariectomized rats (OVX rats) and sham-operated rats (Sham rats). In tissue samples collected at 1.5 h after administration, the liver, adipose tissue, spleen and adrenals showed higher concentrations of radioactivity than the other organs and the plasma. IN bone tissues, the bone marrow (BM) and cancellous tissue (CT) of the femur showed radioactivity concentrations which were higher than that in the plasma, and these increased during repeated administration. Finally, at 24 h after the last dose, the concentrations of radioactivity in bone tissues of older animals (BM, 5,807.2 ng eq/g; CT, 5,264.8 ng eq/g in OVX rats aged 10 months and BM, 11,479.3 ng eq/g; CT, 4,023.0 ng eq/g in OVX rats aged 30 months) were several times higher than those in younger animals (BM, 2,771.6 ng eq/g; CT, 890.2 ng eq/g in 7-week-old untreated rats). The values in OVX rats were also higher than those in Sham rats. Furthermore, micro autoradiography studies of femur sections from OVX rats indicated that [14C] Menaquinone-4 localized in cancellous tissue where bone is known to be actively remodelled. The concentrations of radioactivity in cancellous tissue and bone marrow of OVX rats aged 10 and 30 months were comparable to the pharmacologically effective concentrations of Menaquinone-4 (10(-6)-10(-5) M) in in vitro studies on bone formation. These findings suggest that orally administered Menaquinone-4 distributes specifically into the bone tissues of ovariectomized rats and this is consistent with its effect as a therapeutic agent for osteoporosis.

Aging↗
PubMed1995

[Cyclosporine].

Explore the source record for details and available documents.

Adult↗
PubMed1994

Radioimmunoassay for the novel platelet activating factor receptor antagonist E5880.

A direct radioimmunoassay for E5880, 1-ethyl-2-[[N-(2-methoxybenzoyl)-N-[[(2R)-2-methoxy-3-[[[4- [(octadecylcarbamoyl)- oxy]piperidino]carbonyl]oxy]propoxy]carbonyl]amino]methyl] pyridinium chloride, a novel analogue-type antagonist of platelet activating factor (PAF), was developed. In this procedure, [3H]E5880 was used as the radioligand, and the antiserum was obtained from rabbits immunized with hapten covalently bound to bovine serum albumin. The hapten represents a structural analogue of E5880, with a carboxyl group on the terminal carbon of the 3-position side chain. A metabolite of E5880, deacyl-E5880, cross-reacted weakly (1.8%) with this antiserum. The assay buffer for the radioimmunoassay consisted of PBS, pH 6.5, containing 1% BSA to prevent the degradation of E5880 in aqueous solution and its adsorption to the tube. The detection limit of the assay was 200 pg/mL when a 0.1-mL plasma sample was used. The radioimmunoassay was used for the direct analysis of E5880 in dog plasma. The validity of the radioimmunoassay in dog plasma was demonstrated by comparative analysis of a number of samples by HPLC (r = 0.995, slope = 0.9425). The radioimmunoassay was also used to determine the pharmacokinetics of E5880 in the dog. After the intravenous administration of E5880 (0.2 mg/kg), plasma levels declined biexponentially. The initial plasma half-life, including the distribution phase, was 0.26 h, and the plasma half-life of elimination was 9.96 h.

Adsorption↗
PubMed1994

Development of radioimmunoassay for the novel platelet activating factor receptor antagonist, E6123, and its application to pharmacokinetics in laboratory animals.

A direct radioimmunoassay for the determination of E6123, a novel antagonist of platelet activating factor (PAF) receptor, was developed in order to study the pharmacokinetics at low dose. This procedure used [3H]E6123 as the radioligand and an antiserum obtained from rabbits immunized with the hapten covalently bound to bovine serum albumin. M1B, one of the main metabolites of E6123, exhibited cross-reactivity with antisera. But this metabolite had no effect on measurements of E6123, because the amount of M1B in plasma radioactivity after administration of [14C]E6123 to dogs and monkeys was low. The sensitivity limit of this assay was 25 pg/ml of plasma when 0.1 ml of plasma was used and the assay showed good accuracy and high precision. The validity of the radioimmunoassay was demonstrated by comparative analysis of a number of samples after oral and intravenous administration (1.0 mg/kg) by HPLC-UV method (r = 0.972-0.984, slope = 1.0314-1.2143). The pharmacokinetics of E6123 was studied at a dose of 30 micrograms/kg. After intravenous administration, the plasma concentration-time curves in all species fitted a two-compartment model and the terminal half-lives in guinea pigs, dogs and monkeys (both poor and extensive metabolizers) were 4.77, 1.71, 5.34 and 1.07 h, respectively. After oral administration, the maximum plasma concentrations were obtained within 0.83-3.00 h and the half-life for each animal was almost the same as that after intravenous administration. The mean bioavailabilities of E6123 in guinea pigs, dogs and monkeys (poor and extensive metabolizers) were 106.9, 45.7, 59.1 and 22.8%, respectively.

Animals↗
PubMed1994

[Cyclosporine level in blood as monitored by area-under-the-curve (AUC). III. The influence of absorption phase after orally dosing].

The influence of the absorption phase (the time of maximum blood concentration; Tmax) on the pharmacokinetics of cyclosporine (CYA) in the steady state after oral administration was studied in 26 renal transplant recipients. The patients were divided into three absorption phase groups with the Tmax times as follows, group A (n = 26); OH < or = Tmax < 3 h, group B (n = 6); 3 h < or = Tmax < 6 h and group C (n = 11); 6 h < or = Tmax < or = 12 h. CYA (dose; 1.6-15.0 mg/kg/d) was administered orally to all 26 patients (10-52 years, 33.1-74.2 kg) every 12 h. The blood specimens used in this study were collected just before administration (0 h) in the morning and at intervals of 1, 2, 3, 6, 8 and 12 h after administration. The whole blood CYA levels were measured by high-performance liquid chromatography (HPLC) or by fluorescence polarization immunoassay (FPIA) based on a specific monoclonal antibody. There were no significant differences between the three groups in terms of the dosage (mg/kg/d) and area-under-the-curve (AUC). The trough levels (0, 12 h) correlated well to the AUC only in group A (r = 0.842-0.907, p < 0.001). The morning trough levels (0 h) were significantly higher than the night trough levels (12 h) in groups A and B (p < 0.05-0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

Isolation of a novel substrate-competitive tyrosine kinase inhibitor, desmal, from the plant Desmos chinensis.

In the course of a screening program for tyrosine kinase inhibitors, the chloroform extract of a tropical plant, Desmos chinensis, strongly inhibited the enzyme activity. The active substance was purified by silica gel, gel filtration, and finally crystallized. The structure was elucidated by mass spectrometry and X-ray crystallography to be 8-formyl-2,5,7-trihydroxy-6- methylflavanone, and we named it desmal. Desmal competed with peptide substrate and non-competed with ATP. It inhibited tyrosine kinase in situ in epidermal growth factor (EGF) receptor-overexpressing NIH3T3 (ER12) cells. It also inhibited EGF-induced inositol phosphate formation and morphological changes.

3T3 Cells↗
PubMed1993

Pharmacokinetic characterization of menaquinone-4 in dogs by sensitive HPLC determination.

A simple and sensitive assay method for a pharmacokinetic study of Menaquinone-4 in dogs was established using HPLC with fluorescence detection following extraction with organic solvent. The quantification limit of this method was 1 ng/ml of plasma. A new oily solution formulation of Menaquinone-4 was administered orally to nonfasted dogs at doses of 0.4, 4 and 40 mg/kg. The plasma concentrations reached maximum levels at 1 to 1.5 h after dosing, and then decreased slowly. AUC values up to 24 h after administration were almost dose-proportional. Menaquinone-4 was also administered to dogs in soft-capsules, for comparison with a conventional hard-capsule oral formulation and an intravenous lecithin formulation. The mean AUC for oral dosing in the soft-capsule formulation was 13.5% of that for intravenous dosing in lecithin, and was 4.6 times higher than that for oral dosing in hard-capsules. Additional dosing in fasted dogs indicated that the AUC in pre-fed dogs was about 4 times higher, suggesting that feeding before giving Menaquinone-4 raises the bioavailability. Overall Menaquinone-4 was absorbed rapidly after administration in non-fasted dogs and dose-proportional bioavailability was obtained among the doses of 0.4 to 40 mg/kg. Higher plasma concentrations were observed after administration in the soft-capsule formulation rather than in the hard-capsule formulation. These findings suggest that the soft-capsule formulation would show a good pharmacokinetic profile for elderly patients with osteoporosis.

Administration, Oral↗
PubMed1989

Structure-activity relationship of swainsonine. Inhibition of human alpha-mannosidases by swainsonine analogues.

The inhibitory properties of a series of synthetic epimers and analogues of swainsonine towards the multiple forms of human alpha-mannosidases were studied in vitro and in cells in culture. Of the five epimers tested, only the 8a-epimer and 8,8a-diepimer of swainsonine were specific and competitive inhibitors (Ki values of 7.5 x 10(-5) and 2 x 10(-6) M respectively) of lysosomal alpha-mannosidases in vitro and induced storage of mannose-rich oligosaccharides in human fibroblasts in culture. The structures of these storage products indicated that processing alpha-mannosidases had also been inhibited. This was consistent with the observed inhibition in vitro of these enzymes by these compounds. In contrast, the 8-epimer, 1,8-diepimer and 2,8a-diepimer of swainsonine had no appreciable effect on any alpha-mannosidases. The corresponding open-chain analogues of swainsonine, namely 1,4-dideoxy-1,4-imino-D-mannitol, of the 8a-epimer, namely 1,4-dideoxy-1,4-imino-D-talitol, and of the 8,8a-diepimer, namely 1,4-dideoxy-1,4-imino-L-allitol, were weaker competitive inhibitors of lysosomal alpha-mannosidase, with Ki values of 1.3 x 10(-5), 1.2 x 10(-4) and 1.2 x 10(-4) M respectively. These analogues also proved less effective at inducing oligosaccharide accumulation and in disturbing glycoprotein processing. These compounds offer the opportunity to determine which alterations in the chirality of the swainsonine molecule affect its inhibitory specificity. A comparison of their biological activities has identified reagents that will be useful for studying steps in the biosynthesis and catabolism of glycoproteins and that may be of potential value in chemotherapy.

Alkaloids↗
PubMed1989

Identification of menaquinone-4 metabolites in the rat.

Four metabolites of menaquinone-4 [MQ-4] were isolated from rat urine, bile and liver. From rat urine following intravenous or oral administration of [14C]MQ-4, two major metabolites were isolated and their aglycones were identified as 2-methyl-3-(5'-carboxy-3'-methyl-2'-pentyl)-1,4-naphthoquinone [K acid 1] and 3-(3'-carboxybutyl)-2-methyl-1,4-naphthoquinone [K acid 2]. The aglycone of a third minor metabolite isolated from bile was tentatively identified as 2-methyl-3-(15'-carboxy-3',7',11'-trimethyl-2',6',10', 14'-hexadecatetranyl)-1,4-naphthoquinone [MQ-4-COOH]. The structures of the three aglycones, which were excreted into the urine or bile mainly as glucuronide conjugates, indicated that oxidative degradation of the alkyl side chain of MQ-4 had occurred by omega- and beta-oxidation. In addition, 2,3-epoxy-MQ-4 was identified in the liver of rats which were pretreated with warfarin and then dosed with [14C]MQ-4.

Animals↗
PubMed1989

Effect of solubilizer on the metabolic fate of menaquinone-4 in rats.

Following intravenous administration to rats of all-trans [14C]menaquinone-4 solubilized with purified soybean lecithin [L] or with HCO-60 [H], we examined the effect of the solubilizers on the distribution and excretion of menaquinone-4 [MQ-4]. The level of radioactivity in the liver after dosing with L was about 2 times higher than in dosing with H, and a similar result was obtained in the hepatic microsomal fraction, a target of MQ-4. The rate and amount of biliary excretion of radioactivity after dosing with L were greater than in dosing with H. In addition, the uptake of [14C]MQ-4 by the isolated perfused rat liver was greater with L than H, consistent with the in vivo observation. Further, upon incubation of L or H with hepatic microsomes, the MQ-4 metabolizing enzyme was more highly active toward L than H. These results show that L is more easily transported to the target region, and more rapidly metabolized and excreted into the bile than H, suggesting that the lecithin-solubilized preparation of MQ-4 may be more effective clinically.

Animals↗
PubMed1989

The placental and mammary transport of [14C]menaquinone-4 in rats.

The transfer of menaquinone-4 (vitamin K2(20] to the fetus and milk was studied in pregnant and lactating rats, respectively, after oral administration (4 mg/kg) of [3'-14C]menaquinone-4. Intestinal absorption of menaquinone-4 was rapid and the highest level of radioactivity in each tissue except guts of fetal rats was observed at 4h after dosing. The level in the fetal homogenate was low. At that time, the concentration of menaquinone-4 in the fetal liver was 84 ng/g, corresponding to 9% of the value found in the placenta. Therefore, we conclude that the transfer of menaquinone-4 to the developing rat fetus is restricted by the blood-placenta barrier, but that a sufficient amount of menaquinone-4 (more than the essential amount of vitamin K to ensure full carboxylation) can be transferred into the fetal liver. It was also observed that the radioactivity was transferred to milk after oral administration to lactating rats. Milk/blood concentration ratios at 6 and 24h after dosing were 13.8 and 65.1, respectively. The elimination half-life of radioactivity in milk was about 17h. Eighty-four percent of milk of radioactivity was due to menaquinone-4. These results suggest that the prophylactic maternal oral administration of menaquinone-4 may be efficacious for a prophylaxis of neonatal and infantile vitamin K deficiency.

Animals↗
PubMed1984

Effects of papaverine on the relative distribution of 45Ca ions in subcellular fractions of hog biliary muscles.

The mechanisms by which papaverine (Pap) relaxes smooth muscles of hog bile ducts were investigated with respect to the effects of Pap on the distribution of Ca ions in intracellular organelles. Muscles loaded with 45Ca ions in 139 mM KCl-Tyrode's solution were incubated with Pap, [3H]Pap or theophylline (ThP) in Tyrode's solution. The Pap and Ca contents of various subcellular fractions were measured. Pap (40 microM) had no effect on Ca influx into the muscle in normal and 139 mM KCl-Tyrode's solutions. Pap was distributed to a greater extent in the cytosol fraction (F4) than in microsome and mitochondria-enriched fractions (F3) and in the nuclei-enriched fraction (F2). Pap selectively accumulated in the plasma membrane-enriched fraction (PM-F) and was negligible in the sarcoplasmic reticulum-enriched fraction (SR-F) and the mitochondria-enriched fraction (Mit-F). The Ca release of PM-F was greater and more rapid than the release from SR-F or Mit-F. The increase in the content of Ca in PM-F induced by Pap was enhanced by oxalate, suggesting that the increase is based on the increase in Ca uptake, not on the reduced efflux. Pap increased dose-dependently the Ca content of PM-F and appeared to decrease the Ca contents of SR-F and Mit-F. ThP and cyclic AMP (4 microM) had no effect on the Ca uptake of PM-F and no influence on the effects of Pap. These results suggest that Pap relaxation of hog biliary smooth muscle results from the interaction of the drug with the plasma membrane causing cyclic AMP-independent sequestration of Ca.

Animals↗
PubMed1982

Bis-sulfated gangliotetraosylceramide from rat kidney.

A novel bis-sulfated tetraglycosylceramide containing N-acetylgalactosamine was isolated from the lipid extract of rat kidney. The isolation procedure involved extraction of lipids with chloroform/methanol, alkaline methanolysis, and column chromatographies with DEAE-Sephacel and silica beads. By infrared spectroscopy, proton magnetic resonance spectroscopy, periodate oxidation, solvolysis, chromium trioxide oxidation, and methylation analysis of the native and partially degraded compounds, the structure of this glycolipid is proposed to be (HSO3-3)Gal beta 1-3GalNAc beta 1-4(HSO3-3)Gal beta 1-4Glc beta 1-1Cer. The position of sulfate ester groups and the sequence of carbohydrates were further confirmed by methylation analysis and direct probe mass spectrometry after desulfation-trideuteriomethylation of permethylated glycolipids. The yield of this sulfoglycolipid was 5.5 nmol/g of tissue, which was about 25 and 50 mol %, respectively, of monosulfo-and bis-sulfogangliotriaosylceramide from rat kidney.

Animals↗
PubMed1982

Bis-sulfoglycosphingolipid containing a unique 3-O-sulfated N-acetylgalactosamine from rat kidney.

A novel sulfoglycosphingolipid containing two sulfate ester groups was isolated from the lipid extract of rat kidney. The isolation procedure involved extraction of lipids with chloroform/methanol, alkaline methanolysis, and column chromatographies with DEAE-Sephacel and silica beads. By infrared spectroscopy, proton magnetic resonance spectroscopy, periodate oxidation, solvolysis, chromium trioxide oxidation, and methylation analysis of the native and partially degraded compounds, the structure of this glycolipid is proposed to be (HSO3-3)GalNAc beta 1-4(HSO3-3)Gal beta 1-4Glc beta 1-1Cer. The presence of a unique 3-O-sulfated N-acetylgalactosamine structure was confirmed by gas chromatography-mass spectrometry. The yield of this sulfoglycolipid was 11.2 nmol/g of tissue, which was about half of that of monosulfogangliotriaosylceramide from rat kidney.

Acetylgalactosamine↗
PubMed1982

Isolation and characterization of the sulfated gangliotriaosylceramide from rat kidney.

A sulfoglycosphingolipid containing N-acetylgalactosamine has been isolated from the lipid extract of rat kidney. The isolation procedure involved extraction of lipids with chloroform/methanol, alkaline methanolysis, and column chromatographies with DEAE-Sephadex and Silica beads. The components were N-acetylgalactosamine, galactose, glucose, sphingoid bases, fatty acids, and sulfate in equimolar amounts. The yield of this sulfoglycolipid was about 24 nmol/g of tissue, which was about 13% of that of galactosylceramide 3-sulfate from rat kidney. By infrared spectroscopy, proton magnetic resonance spectroscopy, periodate oxidation, solvolysis, chromium trioxide oxidation, and methylation analysis of the native and partially degraded compound, the structure of this glycolipid is proposed to be GalNAc beta 1--4(HSO3-3)Gal beta 1--4Glc beta 1--1Cer.

Animals↗