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Biomedical subjects

I Yamazaki

Publications and source records attributed to I Yamazaki.

At least 127 records · Page 7Linked to original sources
PubMed1984

Vaginal absorption of a potent luteinizing hormone-releasing hormone analogue (leuprolide) in rats. IV: Evaluation of the vaginal absorption and gonadotropin responses by radioimmunoassay.

The vaginal absorption of leuprolide (a potent luteinizing hormone-releasing hormone analogue), which has the potential for producing regression of hormone-dependent tumors as well as high gonadotropin-releasing and ovulation-inducing activities, was evaluated in rats by radioimmunoassay. Gonadotropin (luteinizing hormone and follicle-stimulating hormone) release was concomitantly determined. Although leuprolide disappeared rapidly from the serum after intravenous administration (the biological half-lives were 8.4 min in the alpha-phase and 33.2 min in the beta-phase), long-lasting serum levels were observed when the analogue was administered vaginally. The vaginal absorption was enhanced by adding citric acid to the test solution. The absolute bioavailability, estimated by the AUC of serum leuprolide levels, was 25.8% over 6 h and 38.0% over 12 h in the 5% citric acid solution (pH 3.5). The sustained release of gonadotropin was also obtained after vaginal administration of the analogue. A linear dose absorption correlation of leuprolide was obtained in the range of 10-1000 micrograms/kg in an aqueous solution or methylcellulose jelly. The release of gonadotropin showed a plateau level at greater than 10 micrograms/kg, which corresponds to an effective dose for antitumor activity. The vaginal absorption of leuprolide varied with the estrous cycle, but this effect was eliminated by prior subcutaneous pretreatment with the analogue.

Absorption↗
PubMed1984

X-ray absorption studies of intermediates in peroxidase activity.

The structures of the enzyme-substrate compounds of peroxidases and catalase determined by X-ray absorption spectroscopy are presented. The valence state of the iron in Compounds I and II is determined from the edge to be higher than Fe+3. A short Fe-Ne (proximal histidine) distance is observed in all forms except Compound II, forcing the Fe-Np average distance to be long, a result which differentiates the peroxidases from the oxygen transport hemoproteins and plays a pivotal role in the mechanism. A correlation is shown between the ratio of peaks in the low k (ligand field indicator ratio) region, the Fe-Np (heme pyrrole nitrogen) average distance, and the magnetic susceptibility, which provides a sensitive indicator of spin state. The mechanism of H2O2 reduction is shown by analysis of the structural changes observed in the intermediates. Possible relationship of these compounds to that of the peroxidatic form of cytochrome oxidase is suggested by these results.

Catalase↗
PubMed1984

The effect of K+ concentration on the energy metabolism in perfused rat heart.

From experiments at various perfusion pressures in hemoglobin-free perfused rat hearts, oxygen consumption and redox shift of pyridine nucleotide were found to vary linearly with cardiac work. This relation was used for analysis of the energy metabolism associated with ion pumps. Mechanical activities such as left ventricular pressure and heart rate varied with the extracellular K+ concentration. Ion-pump dependent changes in oxygen consumption and redox state of pyridine nucleotide, estimated as the difference of the values at normal (4.7 mM) and various other extracellular K+ concentrations with corrections for the change due to mechanical work, were found to vary linearly with the K+ concentration. The slope for oxygen consumption was about 0.1 mumol/min/g X wet wt per mM K+. Lactate release changed markedly but transiently, about 1 min after changing the extracellular K+ concentration, and its amount varied linearly with the K+ concentration. In the steady state, however, lactate release was almost independent of the extracellular K+ concentration, although oxidized pyridine nucleotide increased with increasing K+ concentration. Coronary flow increased with the extracellular K+ concentration. Heart rate changed little between 1 and 12 mM K+, but decreased sharply above 12 mM K+. At 20 mM K+, heart beat was arrested and approximately 40% of myoglobin was deoxygenated. The intracellular oxygen concentration was estimated to be about 10 microM even during aerobic perfusion. Similarly, Ca2+-free arrested heart was found to be in a hypoxic state. The results showed that oxygen entry into cardiac tissue is facilitated by the cardiac cycle.

Animals↗
PubMed1984

Serum concentration patterns of an LHRH agonist, gonadotrophins and sex steroids after subcutaneous, vaginal, rectal and nasal administration of the agonist to pregnant rats.

A highly potent LHRH agonist, des-Gly10-[D-Leu6]-LHRH-ethylamide (TAP-144), was administered by subcutaneous, vaginal, rectal and nasal routes to pregnant rats on Day 10. After subcutaneous administration, almost all the TAP-144 was rapidly absorbed and eliminated. After vaginal administration, the fraction of the dose that reached the systemic circulation, the F value, was very high but the rate of absorption was very low; consequently there was a low peak level and persistence of serum level. After rectal administration, the F value was very low and the rate of absorption was lower than that by the subcutaneous route; consequently the terminal phase half-life was between those of the subcutaneous and vaginal routes. After nasal administration, the F value was also very low but the rate of absorption was enormously high and there was a rapid decrease in serum concentration. The pregnancy-terminating effectiveness of the peptide by these routes of administration was not proportional to the transient high concentrations of the peptide but attributable to its persistence in the serum. Serum LH and FSH concentrations after TAP-144 administration showed similar patterns with the different routes but the peak concentration of LH after vaginal administration was higher than that after other routes. Serum levels of progesterone and oestradiol-17 beta showed small peaks within 2 h after TAP-144 was administered by any route and fluctuated thereafter but the level dropped only in the rats given a dose of TAP-144 that was 100% effective in terminating pregnancy.

Administration, Intranasal↗
PubMed1984

Pathogenicity of newly isolated coxsackievirus B4 for mouse pancreas.

Coxsackievirus B4 fresh isolates from patients with upper respiratory illness and aseptic meningitis were studied for their pathogenicity in the pancreas of SJL/J mice. Out of 12 virus isolates, 7 induced hypoglycaemia in mice 2 to 4 days after virus inoculation. All 3 isolates from faeces of patients induced hypoglycaemia in contrast to 3 viruses isolated from the cerebrospinal fluid which did not. Six isolates from throat swabs were either pathogenic (4 isolates) or non-pathogenic (2 isolates). It is concluded that at least two biologically distinct coxsackieviruses B4 prevail among humans.

Animals↗
PubMed1983

Steady state kinetics and regulation of thyroid peroxidase-catalyzed iodination.

The kinetics of iodination of tyrosine and monoiodotyrosine was studied with purified hog thyroid peroxidase. The Lineweaver-Burk plots and stopped flow kinetic data both yielded a value of about 2 X 10(7) M-1 S-1 as the rate constant for reaction of Compound I with iodide. From Lineweaver-Burk plots, the rate constants for transfer of an assumed enzyme-bound iodinium cation to tyrosine, monoiodotyrosine, and GSH were estimated at 2.1 X 10(6), 3.3 X 10(6), and 3.9 X 10(7) M-1 S-1, respectively. This iodine-transferring reaction was stimulated by thyroxine, triiodothyronine, and diiodothyronine, and the effect increased with the decrease in the number of iodines in the molecules. Diiodotyrosine, during its coupling reaction, inhibited the iodinating reaction by changing the steady state intermediates of thyroid peroxidase from Compound I to Compound II. The quantitative relationship between iodinating and coupling activities of thyroid peroxidase is shown in a scheme, which suggests "preferential formation" of thyroxine from tyrosine by this enzyme system.

Animals↗
PubMed1983

Vaginal absorption of a potent luteinizing hormone-releasing hormone analogue (leuprolide) in rats II: mechanism of absorption enhancement with organic acids.

Organic acids such as citric acid enhance the vaginal absorption of luteinizing hormone-releasing hormone, the potent analogue (leuprolide), and insulin. The mechanism of this absorption enhancement was investigated with leuprolide and hydrophilic markers such as phenol red and Evan's blue. The absorption of the analogue was increased by lowering the pH of the solution and increased more by adding citric, succinic, tartaric, and malonic acids. The absolute bioavailability after vaginal administration of the 5% citric acid solution was 16.7% at pH 3.5 and 38.4% at pH 1.8. The enhancing potency of the absorption correlated well with the chelating ability of the organic acids. The vaginal absorption of phenol red was also enhanced with citric acid and edetic acid, but the enhancing effect of edetic acid was eliminated by adding equimolar calcium ion. These results suggest that the acidifying and chelating abilities of the acids may result in a potent enhancement of the vaginal absorption of leuprolide. A leakage experiment using Evan's blue on the vaginal membrane indicated that the blood-vaginal epithelium barrier was loosened with the administration of citric acid; this change was overcome rapidly.

Absorption↗
PubMed1983

The reaction of carbon monoxide with myoglobin in solution, in an amorphous state, and in crystals.

The stopped flow and flash photolysis methods were applied for the kinetic study of the reaction of carbon monoxide with myoglobin in solution, in an amorphous state, and in crystals. From the flash photolysis data, the reactivity of myoglobin was concluded to be essentially the same in all three states. When the reaction was started with a stopped flow apparatus, the rate became slower as the state of myoglobin was changed from solution to amorphous precipitate, and to crystals. The bigger the crystals, the slower the reaction became. Therefore, the change of the rate could be explained in terms of a diffusion layer formed on the crystals. In the reaction of crystalline myoglobin, the effective concentration of CO was increased locally by about 20 microM after flash photolysis and approached the bulk concentration during the reaction. In contrast, in the reaction of amorphous precipitate of myoglobin, such an increase in the CO concentration was apparently dispersed homogeneously just after flash photolysis.

Animals↗
PubMed1983

Steady-state kinetics of the catalase reaction in the presence of cyanide.

Under carefully controlled experimental conditions, the Michaelis constant for H2O2 was measured to be 1.39 and 1.29 M in the reactions of beef erythrocyte and liver catalases, respectively. These values remained unchanged at temperatures between 1 and 26 degrees C. The turnover number of the Michaelis complex was about 2.25 X 10(7) s-1 for either enzyme at 26 degrees C. The cyanide inhibition in the catalase reaction has been reported to be noncompetitive in spite of the fact that cyanide and H2O2 compete for the same site on the catalase molecule. At high concentrations of H2O2, however, the inhibition became clearly competitive. The existence of the Michaelis complex and the anomalous features of cyanide inhibition were clearly accounted for on the basis of simple kinetic models. At H2O2 concentrations below 100 mM, the catalase reaction obeyed first order kinetics with respect to H2O2 and its apparent second order rate constant was measured to be 7.6 X 10(6) and 7.9 X 10(6) M-1 . S-1 for erythrocyte and liver catalases, respectively.

Animals↗
PubMed1983

The effect of intracellular oxygen concentration on lactate release, pyridine nucleotide reduction, and respiration rate in the rat cardiac tissue.

By measuring the absorbance change due to myoglobin oxygenation in hemoglobin-free isolated perfused rat hearts, we analyzed effects of perfusion pressure and heart rate upon the intracellular oxygen concentration. With Langendorff perfusion, the cardiac tissue was kept normoxic (above 50 microM O2) at aortic pressure above 50 cm H2O, but became hypoxic (8 microM O2) at 30 cm H2O. The increase in cardiac work, expressed as the product of peak systolic pressure and heart rate, increased oxygen consumption at aortic pressure of 50-200 cm H2O. The heart was kept normoxic under these conditions. Lactate release, oxygen consumption, and the oxidation-reduction state of pyridine nucleotide were measured as a function of myoglobin oxygenation under various normoxic and anoxic conditions. Pyridine nucleotide fluorescence and lactate release started to increase as the intracellular oxygen concentration decreased to 6 and 10 microM, respectively. Oxygen consumption was kept constant until the oxygen concentration decreased to 10 microM and slowed down below it. A close relationship between oxygen consumption and lactate release was observed. Infusions of epinephrine and norepinephrine under normoxic perfusion conditions increased cardiac work, oxygen consumption, and lactate release. More than 50% of myoglobin was then deoxygenated even under normoxic perfusion conditions. The increase in lactate release was ascribable to the increase in glycolytic flux caused by hypoxia. The change of pyridine nucleotide fluorescence by epinephrine was also explained by hypoxia in cardiac tissue.

Animals↗
PubMed1983

Desensitization of gonadotropin-releasing response following vaginal consecutive administration of leuprolide in rats.

The vaginal absorption of a potent luteinizing hormone-releasing hormone analog (leuprolide), and the gonadotropins (luteinizing hormone and follicule-stimulating hormone)-releasing response after continuous vaginal and subcutaneous administration of the analog to rats were determined by the radioimmunoassay. A marked suppressive effect on the gonadotropin-releasing response along with long-lasting serum levels of leuprolide were paradoxically observed after consecutive 3-d vaginal administration of the analog at doses of 1 microgram/kg or greater. Pituitary function recovered progressively with cessation of the treatment but was not complete 4 d after cessation. Continuous vaginal and subcutaneous infusion resulted in an almost complete inhibition of both gonadotropins response. It is suggested that effective desensitization of the pituitary gonadotropin response is elicited by continuous administration of leuprolide and, therefore, the vaginal administration resulting in prolonged serum levels of the analog could be preferable as a self-administration method for medical treatments such as anti-tumor therapy and birth control.

Absorption↗
PubMed1982

One- and two-electron oxidations of tyrosine, monoiodotyrosine, and diiodotyrosine catalyzed by hog thyroid peroxidase.

Stopped flow experiments were carried out with purified hog thyroid peroxidase (A413 nm/A280 nm = 0.42). In the steady state of oxidations of L- and D-tyrosines, N-acetyltyrosinamide, and monoiodotyrosine, thyroid peroxidase existed in the form of Compound I, the primary catalytic intermediate of peroxidase in its reaction with H2O2. Kinetic results led us to conclude that thyroid peroxidase catalyzes two-electron oxidations of these molecules. In the steady state of oxidation of diiodotyrosine, on the other hand, the enzyme was found in the form of compound II at pH 7.4, but in the form of compound I at pH 5.5. The result implies that the mechanism of diiodotyrosine oxidation varied from a one-electron to a two-electron type as the pH decreased. The selection of mechanisms of oxidation appears to be peculiar to thyroid peroxidase; horseradish peroxidase and lactoperoxidase catalyzed only one-electron oxidations of these five donor molecules. Rate constants for rate-limiting steps in the reactions of these donor molecules with the three peroxidases were measured by overall kinetic and stopped flow kinetic methods.

Animals↗
PubMed1982

The reactivity of Mg-substituted horseradish peroxidases.

Mg-substituted horseradish peroxidases were oxidized by K2IrCl6 or K3Fe(CN)6 to their porphyrin radical form and the 1:1 stoichiometric relationship was confirmed by spectrophotometric, fluorophotometric, and ESR titration methods. The values of E'0 for oxidations of Mg peroxidases A and C were both 0.63 V at pH 6 and depended on pH in the same way as postulated for the Compound I/Compound II couples of the corresponding enzymes. Unlike Zn peroxidase C, Mg peroxidase C was not directly oxidized by H2O2. The oxidation was catalyzed by the native peroxidase. Mg peroxidase C was photooxidized to the radical form faster than Zn peroxidase C, but its oxidation was accomplished by irreversible changes in the porphyrin in the early stage of reaction. The rate of reduction of the oxidized Mg peroxidases in the presence of various electron donors was measured at varying pH values and compared with the rate of Compound I reduction. A role of porphyrin as a site of electron transfer in the peroxidase catalysis was suggested.

Electron Spin Resonance Spectroscopy↗
PubMed1982

Reactions of purified hog thyroid peroxidase with H2O2, tyrosine, and methylmercaptoimidazole (goitrogen) in comparison with bovine lactoperoxidase.

Stopped flow experiments were carried out with purified hog thyroid peroxidase (A413 nm/A280 nm = 0.42). It reacted with H2O2 to form Compound I with a rate constant of 7.8 X 10(6) M-1 s-1. Compound I was reduced to Compound II by endogeneous donor with a half-life of 0.36 s. Compound I was reduced by tyrosine directly to the ferric enzyme with a rate constant of 7.5 X 10(4) M-1 s-1. Tyrosine could also reduce Compound II to the ferric enzyme with a rate constant of 4.3 X 10(2) M-1 s-1. Methylmercaptoimidazole accelerated the conversion of Compound I to Compound II and reacted with Compound II to form an inactivated form, which was discernible spectrophotometrically. The reactions of thyroid peroxidase with methylmercaptoimidazole quite resembled those of lactoperoxidase, but occurred at higher speeds. The absorption spectra of thyroid peroxidase were similar to those of lactoperoxidase and intestinal peroxidase, but obviously different from those of metmyoglobin, horseradish peroxidase, and chloroperoxidase. Similarity and dissimilarity between thyroid peroxidase and lactoperoxidase are discussed.

Animals↗
PubMed1982

Vaginal absorption of a potent luteinizing hormone-releasing hormone analog (leuprolide) in rats I: absorption by various routes and absorption enhancement.

The absorption of a potent luteinizing hormone-releasing hormone analog (leuprolide) through different routes was evaluated by determining the ovulation-inducing activity in diestrous rats. Vaginal administration showed the greatest potency among nonparenteral routes and was followed successively by rectal, nasal, and oral administration. Mixed micellar solution with monoolein-bile acids improved the intestinal absorption of leuprolide, and nasal absorption was enhanced by adding sodium glycocholate, surfactin, or polyoxyethylene 9 lauryl ether, but these bioavailabilities were still insufficient. The vaginal absorption was enhanced by organic acids: citric, succinic, tartaric, and glycocholic; the absolute bioavailability increased to approximately 20%. The vaginal absorption from jellies, as practical dosage forms, yielded sufficient activity of leuprolide, but absorption was slightly reduced with highly polar polymers or with higher concentrations of polymers. It was concluded that vaginal administration of leuprolide can be a rational dosage method for a long-term antitumor therapy.

Absorption↗
PubMed1982

Preparation of bovine milk xanthine oxidase as a dehydrogenase form.

When xanthine oxidase was prepared from fresh raw cow's milk in the presence of dithioerythritol, 94% of its xanthine-oxidizing activity was found as a dehydrogenase type. The enzyme was reversibly converted to an oxidase type when dithioerythritol was removed. The conversion was ascribable to the oxidation of sulfhydryl groups of the enzyme by oxygen. The two forms of the enzyme gave the same visible spectrum, but the dehydrogenase form alone gave a characteristic difference spectrum upon addition of NAD+. NADH served as a good electron donor for the dehydrogenase form of the enzyme but not for the oxidase form. When xanthine was used as an electron donor, the overall rate of p-benzoquinone reduction was the same for the oxidase and dehydrogenase forms, but the proportion of one-electron flux from the enzyme to p-benzoquinone was considerably greater in the reaction of the dehydrogenase form than in that of the oxidase form.

Animals↗