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Biomedical subjects

K Akamatsu

Publications and source records attributed to K Akamatsu.

At least 19 recordsLinked to original sources
PubMed2006

Improvement of pulmonary function and dyspnea by tiotropium in COPD patients using a transdermal beta(2)-agonist.

BACKGROUND: A combination of bronchodilators may be effective in the treatment of chronic obstructive pulmonary disease (COPD). We examined the effect of adding a long-acting anti-cholinergic agent (tiotropium) to a transdermal-type beta(2)-agonist (tulobuterol) on dyspnea as well as pulmonary function. METHODS: In a multicentre, randomized, parallel design study, 60 COPD patients treated with the transdermal beta(2)-agonist tulobuterol were divided into a tiotropium added group (Tulo+Tio group, n=40) or transdermal beta(2)-agonist tulobuterol alone group (Tulo group, n=20), and then treated for 4 weeks after a 2 week run-in period. Pulmonary function and a dyspnea (Medical Research Council (MRC)) scale were assessed before and after the treatment. Daily peak expiratory flow (PEF) monitoring was also performed. RESULTS: After 4 weeks, the Tulo+Tio group showed a significant increase in pulmonary function compared with the Tulo group; DeltaFVC (0.31+/-0.06 L vs. 0.06+/-0.05 L, p< 0.01), DeltaFEV(1) (0.15+/-0.03 L vs. -0.02+/-0.02 L, p<0.0001), and DeltaPEF (41.0+/-5.1 L/min vs. 0.5+/-3.5 L/min, p<0.0001). The MRC dyspnea scale was also significantly improved in Tulo+Tio, but not in Tulo group. CONCLUSION: These results suggest that tiotropium caused a significant improvement in both pulmonary function and dyspnea in COPD patients already treated with the transdermal beta(2)-agonist tulobuterol.

Administration, Cutaneous↗
PubMed2006

Inhibition of reactive nitrogen species production in COPD airways: comparison of inhaled corticosteroid and oral theophylline.

BACKGROUND: Reactive nitrogen species (RNS) are thought to be one of the important factors in the pathogenesis of chronic obstructive pulmonary disease (COPD). A study was undertaken to examine the effects of theophylline and fluticasone propionate (FP) on RNS production in subjects with COPD. METHODS: Sixteen COPD subjects participated in the study. Theophylline (400 mg/day orally) or FP (400 mug/day inhalation) were administered for 4 weeks in a randomised crossover manner with a washout period of 4 weeks. Induced sputum was collected at the beginning and end of each treatment period. 3-nitrotyrosine (3-NT), which is a footprint of RNS, was quantified by high performance liquid chromatography with an electrochemical detection method as well as by immunohistochemical staining. RESULTS: Theophylline significantly reduced the level of 3-NT in the sputum supernatant as well as the number of 3-NT positive cells (both p<0.01). FP also reduced 3-NT formation, but the effect was smaller than that of theophylline. Theophylline also significantly reduced the neutrophil cell counts in the sputum (p<0.01), while FP treatment had no effect on the number of inflammatory cells in the sputum, except eosinophils. CONCLUSIONS: Theophylline reduces nitrative stress and neutrophil infiltration in COPD airways to a larger extent than inhaled corticosteroid.

Administration, Inhalation↗
PubMed2005

Pharmacodynamic equivalence study of CFC-free and CFC-containing procaterol hydrochloride metered-dose inhalers.

Equivalence between a CFC-free procaterol hydrochloride metered-dose inhaler using HFA-227 as a propellant (Meptin [HFA]) and a CFC-containing procaterol hydrochloride metered-dose inhaler (Meptin [CFC]) was assessed in 28 patients with bronchial asthma. The study was conducted in a randomized, double-dummy, double-blind crossover manner, using forced expiratory volume in the first second (FEV1) as an index of bronchodilatory effect. In Period I, the patients received 20 microg of either Meptin [HFA] or Meptin [CFC] and then crossed over in Period II after a washout interval of 3-28 days. Pharmacodynamic equivalence was assessed using AUC (FEV1)/h and peak FEV1 as indices, and the data was analyzed by analysis of variance. Factors used for the analysis were the treatment group and/or carryover effect, patients within each group, period, and treatment. The 90% confidence intervals for the differences between the two treatments were -0.0507 to 0.0039 (L) for mean AUC (FEV1)/h and -0.056 to 0.026 (L) for mean peak FEV1, both within the acceptance criteria of -0.15 to 0.15 (L). Meptin [HFA] was therefore assessed as being equivalent to the current Meptin [CFC].

Administration, Inhalation↗
PubMed2001

Synthesis and pharmacological activity of a novel water-soluble hepatocyte-specific polymeric prodrug of prostaglandin E(1) using lactosylated poly(L-glutamic hydrazide) as a carrier.

A novel polymeric prodrug of prostaglandin E(1) (PGE(1)) was synthesized using lactosylated poly(L-glutamic hydrazide) (Lac-NH-PLGA) as a targetable carrier to hepatocytes. Poly(L-glutamic hydrazide) (PLGA-HZ) was prepared by reacting poly(gamma-benzyl-L-glutamate) with hydrazine monohydrate, followed by coupling with lactose via a hydrazone linkage. Then the lactosylated PLGA-HZ was reduced by sodium cyanoborohydride (NaBH(3)CN) in order to make the linkage irreversible (Lac-NH-PLGA). Finally, PGE(1) was bound to hydrazide moieties remaining in Lac-NH-PLGA without any condensing agent under weakly acidic conditions (pH 5) where PGE(1) would be chemically most stable at room temperature (PGE(1) conjugate). The PGE(1) conjugate prepared was sufficiently water-soluble in spite of the hydrophobic nature of its backbone (-NH-CH-CO-) and PGE(1) itself. After intravenous injection in mice, the [111In]PGE(1) conjugate rapidly accumulated in the liver, whereas [111In]PLGA-HZ did not, suggesting the involvement of a galactose-specific mechanism in the uptake of the [111In]PGE(1) conjugate. Fractionation of liver cells revealed that the [111In]PGE(1) conjugate was preferentially taken up by liver parenchymal cells. The pharmacological activity was examined in mice with fulminant hepatitis induced by intraperitoneal injection of carbon tetrachloride. Intravenous injection of the PGE(1) conjugate at a dose of 1 mg (0.065 mg PGE(1))/kg effectively inhibited the increase in plasma glutamic pyruvic transaminase (GPT) activity compared with that of free PGE(1) at a dose of 0.065 or 0.65 mg/kg. These results suggest that the PGE(1) conjugate is an excellent prodrug for the treatment of fulminant hepatitis.

Acute Disease↗
PubMed2001

X-ray absorption near-edge structure (XANES) spectral changes of 2-deoxy-D-ribose by irradiation within the energy region around the oxygen K-shell absorption edge.

The physicochemical characteristics of 2-deoxy-D-ribose moieties in DNA strands are important to understand biological radiation stress. So, the X-ray absorption near edge structure (XANES) of 2-deoxy-D-ribose within the energy region around the oxygen K-shell absorption edge was measured. 2-deoxy-D-ribose was exposed to 3 energies of X-rays, i.e., 526.3 eV (below O 1s-->pi*), 537.8 eV (at the absorption peak of O 1s-->sigma*) and 552.6 eV (above O 1s-->sigma*) for given periods. Slight differences in spectral changes were seen in the each irradiation energy, suggesting in fact that the chemical state and following rearranged chemical structure of 2-deoxy-D-ribose may be different between the 3 irradiation energies.

DNA↗
PubMed2001

X-ray absorption near edge structures of DNA or its components around the oxygen K-shell edge.

The initial process of radiation damage in DNA was investigated by measuring the X-ray absorption near edge structures (XANES) within the energy region around the oxygen K-shell absorption edge for DNA, cytosine and 2-deoxy-d-ribose. Irradiation and XANES experiments were performed with the BL23SU soft X-ray beamline, using synchrotron radiation from the 8 GeV electron storage ring at SPring-8. Samples were mounted on gold-coated plates in a vacuum chamber. The XANES spectra were obtained by measuring the photoelectron current of the samples. 2-Deoxy-d-ribose was exposed to X rays at the absorption peak corresponding to the oxygen (O) 1s-->sigma* transition energy (538 eV); the XANES spectra were obtained after each irradiation. DNA and cytosine, possessing characteristic XANES spectra, both had two major energy bands corresponding to the O 1s-->pi* and 1s-->sigma* transitions. Two new peaks appeared and gradually increased in the XANES spectra of 2-deoxy-d-ribose during irradiation. These results suggest that C-O bonds in 2-deoxy-d-ribose are transformed to C=O bonds by O 1s-->sigma* transition, suggesting that the molecules undergo chemical changes into carbonyl-containing compounds.

DNA↗
PubMed2000

Polyglutamation of antifolates is not required for induction of extracellular release of adenosine or expression of their anti-inflammatory effects.

Methotrexate (MTX) exerts an anti-inflammatory effect, reportedly by enhancing the release of adenosine, through an accumulation of 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR). To examine the role of polyglutamation in promoting anti-inflammatory effects by antifolates, we tested whether a new antifolate designed to be resistant to intracellular polyglutamation (MX-68) exhibited anti-inflammatory effects and stimulated adenosine release. Both MX-68 and MTX (at concentrations greater than 0.1 microM) increased the release of adenosine from Daudi cells in vitro. Inhibition of AICAR synthesis suppressed adenosine release by MX-68 and MTX. The anti-inflammatory effects of antifolates were estimated using the murine air pouch model, in which a BALB/c mouse was intraperitoneally injected with MX-68 or MTX once a week for 3 weeks. MX-68 (0.5 mg kg(-1) week(-1)), as well as MTX, inhibited infiltration of leukocytes into the air pouch. This inhibitory effect was suppressed in the presence of an adenosine A(2) receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX). These results suggest that MX-68, like MTX, exerts anti-inflammatory effects through the accumulation of AICAR and release of adenosine. These results suggest that polyglutamation of antifolate is not required for expression of anti-inflammatory effects.

2-Aminoadipic Acid↗
PubMed2000

Design of polymeric prodrugs of PGE1 for cell-specific hepatic targeting.

Based on the relationship between in vivo disposition of macromolecules and their physicochemical and biological characteristics obtained through clearance concept-based pharmacokinetic analysis, polymeric prodrugs of prostaglandin E1 (PGE1) were designed stepwise and evaluated on their targeting and therapeutic efficiencies. Although galactosylated poly-L-glutamic acid with a ethylene diamine (ED) spacer (Gal-ED-PLGA) showed good targeting efficacy in mice, its PGE1 conjugate synthesized by the carbonyldiimidazole method failed to show therapeutic effects probably due to inactivation of PGE1 during conjugation and lack of release in the tissue. In order to overcome these problems, PGE1 was conjugated to galactosylated poly-(L-glutamic acid) hydrazide (Gal-HZ-PLGA) via hydrazone bond. The PGE1-Gal-HZ-PLGA conjugate labeled with [111In] or [3H]PGE1 rapidly accumulated in the liver parenchymal cells after intravenous injection. In addition, PGE1 conjugate effectively inhibited the increase of GPT level in plasma, while free PGE1 indicated no therapeutic efficacy even at more than ten times higher doses, in carbon tetrachloride-induced hepatitis mice. These findings suggest potentials of polymeric targeting systems of PGE1 to hepatocyte utilizing galactose recognition.

Acute Disease↗
PubMed1999

Design of polymeric prodrugs of prostaglandin E(1) having galactose residue for hepatocyte targeting.

Based on the relationship between in vivo disposition of macromolecules and their physicochemical and biological characteristics obtained through clearance concept-based pharmacokinetic analysis, polymeric prodrugs of prostaglandin E(1)(PGE(1)) were designed stepwise and evaluated on their targeting and therapeutic efficiencies. First poly-L-lysine (PLL) and poly-L-glutamic acid (PLGA) with an ethylenediamine (ED) spacer were modified with 2-imino-2-methoxyethyl 1-thiogalactoside to obtain galactosylated derivatives. After intravenous injection in mice, Gal-ED-PLGA was selectively taken up by the liver parenchymal cells via receptor-mediated endocytosis, while Gal-PLL accumulated in the liver as well as PLL mostly due to electrostatic interaction. Although Gal-ED-PLGA showed good targeting efficacy, its PGE(1) conjugate synthesized with activated PGE(1) by carbonyldiimidazole method failed to show therapeutic effects probably due to inactivation of PGE(1) during conjugation and lack of release in the tissue. In order to overcome these problems, we next conjugated PGE(1) to galactosylated poly-(L-glutamic acid) hydrazide (Gal-HZ-PLGA) in which PGE(1) was easily coupled to Gal-HZ-PLGA via a hydrazone bond in weak acidic solution (pH 5) at room temperature. The PGE(1)-Gal-HZ-PLGA conjugate labeled with [(111)In] or [(3)H]PGE(1) rapidly accumulated in the liver parenchymal cells. In addition, the PGE(1) conjugate effectively inhibited the increase of the GPT level in plasma, while free PGE(1) indicated no therapeutic efficacy even at more than ten times higher doses, in carbon tetrachloride-induced hepatitis mice. These findings suggest potentials of polymeric targeting systems of PGE(1) to hepatocyte utilizing galactose recognition.

Alprostadil↗
PubMed1999

TEM Investigation and Electron Diffraction Study on Dispersion of Gold Nanoparticles into a Nylon 11 Thin Film during Heat Treatment.

We have investigated the effect of heat treatment on the changes in the microstructure of nylon 11 thin films containing nanosized Au particles by means of lateral and cross-sectional transmission electron microscopy. It was observed that, on heat treatment, the Au islandlike particles initially deposited on the nylon 11 surface penetrated into the polymer layer to form a composite film consisting of nanosized spherical Au particles dispersed in a polymer matrix, while the initially amorphous nylon 11 matrix crystallized to the alpha-crystalline form. The surface stress coefficient of the Au particles, calculated from the lattice constant determined by the electron diffraction patterns, decreased as the Au particles penetrated into the polymer matrix, which can be due to both coalescence of the particles to a spherical shape and reduction of the surface free energy of the particles by embedding in the matrix. The molecular chain motion of the nylon 11 matrix during the crystallization process is suggested to be responsible for the dispersion of Au particles into the polymer matrix. Copyright 1999 Academic Press.

Journal Article↗
PubMed1999

Novel Preparation Method for Nano-Sized Gold Particles by Using NH2-Terminated Polyethyleneoxide.

Nano-sized gold particles dispersed in a composite were prepared by using NH2-terminated polyethyleneoxide (PEO-NH2) as a matrix. Gold was vapor-deposited onto a melt of PEO-NH2. Gold was smoothly dispersed into the interior of PEO-NH2 to form nano-sized gold particles. After cooling the melt to room temperature, a stable solid composite was obtained. The composite readily dissolved in water or various kinds of organic solvents to produce a stable colloidal solution. The mean size of the gold particles was 3.4 nm, and the content of gold was ca. 5 wt%. Copyright 1999 Academic Press.

Journal Article↗
PubMed1999

Synthesis and pharmacokinetics of a novel macromolecular prodrug of Tacrolimus (FK506), FK506-dextran conjugate.

A novel macromolecular prodrug of Tacrolimus (FK506), FK506-dextran conjugate, was developed and its physico-chemical, biological and pharmacokinetic characteristics were studied. The conjugate was estimated to contain 0.45% of FK506 and the coupling molar ratio was approximately 1:1 (dextran-FK-506). Adsorption experiments using ion exchangers indicated that FK506-dextran conjugate acted as a weakly negatively charged macromolecule. Low molecular weight radioactive compound(s), which was eluted in the same fractions as [(3)H]FK506, was released from [(3)H]FK506-dextran conjugate by chemical hydrolysis with a half-life of 150 h in phosphate buffer. In vitro immunosuppressive activity of the conjugate, as assessed by the rat lymphocyte stimulation test, was almost comparable to that of free FK506, suggesting that biologically active FK506 could be liberated from the conjugate. In vitro biodistribution studies demonstrated that conjugation with the dextran derivative dramatically changed the pharmacokinetic properties of FK506 after intravenous injection in rats. AUC of the FK506-dextran conjugate was almost 2000 times higher than that of free FK506 and organ uptake clearances of the conjugate were significantly smaller than those of the free drug. Thus, the present study has demonstrated that the FK506-dextran conjugate behaves as a prodrug of FK506 with an extended blood circulating time and can be expected to have an improved therapeutic potency.

Animals↗
PubMed1999

Development of a hepatocyte-specific prostaglandin E(1) polymeric prodrug and its potential for preventing carbon tetrachloride-induced fulminant hepatitis in mice.

A polymeric prodrug of prostaglandin E(1) (PGE(1)) was synthesized using galactosylated poly(L-glutamic acid hydrazide) (Gal-HZ-PLGA) as a biodegradable and targetable carrier to hepatocytes. Poly(L-glutamic acid hydrazide) was prepared by reacting poly(gamma-benzyl-L-glutamate) with hydrazine monohydrate, followed by reaction with 2-imino-2-methoxyethyl-1-thiogalactosides to obtain Gal-HZ-PLGA after i.v. injection. (111)In-labeled galactosylated poly(L-glutamic acid hydrazide) ((111)In-Gal-HZ-PLGA) rapidly accumulated in the liver in a dose-dependent manner, whereas (111)In-poly(L-glutamic acid hydrazide) did not, indicating the involvement of a galactose-specific mechanism in the uptake of (111)In-Gal-HZ-PLGA. Fractionation of liver cells revealed that (111)In-Gal-HZ-PLGA was preferentially taken up by liver parenchymal cells. After being taken up by the liver, (111)In-Gal-HZ-PLGA was gradually degraded, and radioactive metabolites with low molecular weight were detected within 10 min after injection. Then, PGE(1) or [(3)H]PGE(1) was coupled to Gal-HZ-PLGA via a hydrazone bond under mild conditions to obtain PGE(1) conjugate. After i.v. injection, [(3)H]PGE(1) conjugate was rapidly taken up by the liver (more than 80% of the dose). After injection of the conjugate, (3)H radioactivity remained in the liver, representing about 70% of the dose, even at 24 h, whereas little radioactivity remained in the organ at 1 h after the injection of free [(3)H]PGE(1). Finally, its pharmacological activity was examined in mice with fulminant hepatitis induced by peritoneal injection of carbon tetrachloride. The i.v. injection of PGE(1) conjugate at a dose of 1 mg (0.074 mg PGE(1))/kg effectively inhibited the increase of plasma glutamic pyruvic transaminase activity, whereas twice this dose (0.15 mg/kg) of free PGE(1) had little effect. These results suggest that the PGE(1) conjugate is an excellent polymeric prodrug of PGE(1) for hepatitis therapy.

Acute Disease↗
PubMed1998

Disposition characteristics of glycosylated poly(amino acids) as liver cell-specific drug carrier.

Potentials of glycosylated poly(amino acids) as carriers of drugs and/or polynucleotides to the liver were studied in mice in detail. Poly-L-glutamic acid (PLGA) and poly-L-lysine (PLL) were selected as carrier backbones and modified with 2-imino-2-methoxyethyl 1-thiogalactoside or mannoside to obtain galactosylated and mannosylated derivatives. After intravenous injection in mice at a dose of 1 mg/kg, Gal-PLGA and Man-PLGA were selectively taken up by the liver parenchymal cells (PC) and liver nonparenchymal cells (NPC), respectively. Moreover, the uptake of Gal-PLGA and Man-PLGA by the liver were significantly inhibited by the presence of Gal-BSA and Man-BSA, respectively. On the other hand, PLL was targeted to the liver without glycosylation. However, Gal-PLL and Man-PLL showed higher accumulation in the liver than unmodified PLL. Although Gal-PLL and Man-PLL showed different distribution between PC and NPC from that of PLL, the effect of the modifications was less pronounced than the cases of PLGA derivatives. In addition, these glycosylated poly(amino acids) investigated, regardless of the type of amino acid or the sugar grafted, were rapidly degraded to be eluted in the low molecular weight fractions in a gel filtration chromatography. These results suggest that glycosylated PLGAs can be useful carriers of low molecular drugs to the liver cells through conjugation, while glycosylated PLLs could be targetable carriers to the cells after the reduction of their cationic charge by complex formation with polynucleotides.

Animals↗
PubMed1998

Significant role of the increase in renin-angiotensin system in cardiac hypertrophy and renal glomerular sclerosis in double transgenic tsukuba hypertensive mice carrying both human renin and angiotensinogen genes.

Tsukuba hypertensive mice (THM) are a hypertensive model prepared by mating a transgenic mice with human renin gene and a transgenic mice with human angiotensinogen gene. In the present study, we examined effects of renin-angiotensin system (RAS) on cardiac hypertrophy and renal disorders using Tsukuba hypertensive mice. While THM showed an increase of about 30 mmHg in systolic pressure compared to C57BL/6 mice employed as normal control animals, the increase in blood pressure was not observed in the mice to which either gene was transferred. Urinary volume, water intake volume, urinary albumin excretion, heart to body weight ratio and renal glomerular sclerosis index increased significantly in THM, but none of these parameters showed a significant difference from the C57 mice when they were examined in mice to which either of the genes was transferred. In contrast, when lisinopril was administered to THM, all the parameters decreased significantly without lowering the systolic pressure. From these findings, it was demonstrated that RAS was playing a significant role in cardiac hypertrophy and renal disorders of THM and that lisinopril had inhibitory effects on cardiac hypertrophy and renal glomerular sclerosis by inhibiting RAS.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

[Squamous cell lung cancer with minimal-change nephrotic syndrome].

We report a case of squamous cell lung cancer with nephrotic syndrome. A 69-year-old man was admitted because of proteinuria and microhematuria. A plain chest X-ray film on admission showed a large mass in the left-lower lung field. The patient was given a diagnosis of minimal-change-nephrotic syndrome and squamous cell lung cancer. We first treated the nephrotic syndrome with glucocorticoid therapy, and then treated the lung cancer with chemo-radiotherapy. This reduced the lung cancer, alleviated the proteinuria, and completely resolved the nephrotic syndrome. Nephrotic syndrome is generally associated with malignant lymphoma and other nonepithelial neoplasms. As the underlying disease, epithelial neoplasms are less common, but lung cancer is one of the most widely reported. Histologically, most cases of cancer-associated nephrotic syndrome exhibit membranous nephropathy; Minimal-change nephrotic syndrome is rare. Deposits of immunocomplex on glomerular basement membrane are considered to play a pathogenic role in membranous nephropathy. However, the pathogenesis of minimal-change nephrotic syndrome is different.

Aged↗