Folia Pharmacologica Japonica
Online ISSN : 1347-8397
Print ISSN : 0015-5691
ISSN-L : 0015-5691
Volume 122, Issue 2
Displaying 1-6 of 6 articles from this issue
Award Lecture
  • Shinji TAKAI
    Article type: Award Lecture
    2003 Volume 122 Issue 2 Pages 111-120
    Published: 2003
    Released on J-STAGE: July 22, 2003
    JOURNAL FREE ACCESS
    In vascular tissues, angiotensin II is cleaved from angiotensin I by chymase and angiotensin converting enzyme (ACE). In the normal state, chymase is stored in mast cells and has no angiotensin II-forming activity, while chymase is activated immediately where mast cells have been activated by local stimuli. A clinical trial of an angiotensin receptor blocker (ARB) for preventing restenosis after percutaneous transluminal coronary angioplasty was successful, but that of an ACE inhibitor was not. After balloon injury in dog vessels, chymase activity was significantly increased in the injured artery, and a chymase inhibitor and an ARB were effective in preventing the vascular proliferation, but an ACE inhibitor was ineffective. In dog grafted veins, intimal area, chymase activity, and angiotensin II concentration were significantly increased after the operation, while they were significantly suppressed by a chymase inhibitor. However, the chymase inhibitor, unlike ACE inhibitor and ARB, did not affect blood pressure. These reports indicate that local angiotensin II production by chymase is involved only in the injured vessels. Therefore, a chymase inhibitor may be useful for preventing vascular disorders without affecting blood pressure.
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Thesis
  • Tohru NOJI, Akira KARASAWA, Hideaki KUSAKA
    Article type: Thesis
    2003 Volume 122 Issue 2 Pages 121-134
    Published: 2003
    Released on J-STAGE: July 22, 2003
    JOURNAL FREE ACCESS
    Adenosine protects against cellular damage and dysfunction under several adverse conditions, including inflammation. We examined the effects of KF24345, a novel adenosine uptake inhibitor, on inflammatory diseases to investigate whether the adenosine uptake inhibition is useful for the treatment of inflammation. KF24345 inhibited adenosine uptake into washed erythrocytes (in vitro) and sampled blood cells from mice after its oral administration (in vivo). KF24345 significantly suppressed lipopolysaccharide-induced tumor necrosis factor-α production and leukopenia in mice, and the effects of KF24345 were abolished by the treatment with a non-selective or an A2A-selective adenosine receptor antagonist. In the experimental glomerulonephritis induced in mice by anti-glomerular basement membrane antiserum, KF24345 significantly inhibited proteinuria and glomerular damage without exhibiting the side effects observed following the treatment with prednisolone and cyclophosphamide. In addition, KF24345 ameliorated the severity of experimental acute pancreatitis induced by cerulein or choline-deficient and ethionine-supplemented diet in mice, and it decreased mortality accompanying severe acute pancreatitis. The anti-pancreatitis effects of KF24345 were abolished by the treatment with a non-selective or an A2A-selective adenosine receptor antagonist. These results suggest that KF24345 and adenosine uptake inhibitors can be a new therapeutic approach for various inflammatory diseases, including glomerulonephritis and acute pancreatitis.
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Technical Note
  • Yukio AGO, Toshio MATSUDA
    Article type: Technical Note
    2003 Volume 122 Issue 2 Pages 135-140
    Published: 2003
    Released on J-STAGE: July 22, 2003
    JOURNAL FREE ACCESS
    Brain microdialysis has become a well established and a widely-used technique for in vivo measurement of extracellular levels of neurotransmitters. However, a single neurotransmitter in the perfusates has been measured in most studies. The present paper describes a simultaneous measurement of serotonin and dopamine release in the prefrontal cortex of mice. Using this technique, we examined the modulation by serotonin1A receptors of serotonin, dopamine, and noradrenaline release in the cortex of isolation-reared mice. The isolation-reared mouse is a useful model of complicated mood disorders including phenotypes of anxiety, depression, and aggression. The study shows that isolation rearing selectively decreases the sensitivity of serotonin1A receptors to increase dopamine release.
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Review on New Drug
  • Mitsuharu HANADA, Toshihiro NOGUCHI, Takao MURAYAMA
    Article type: Review on New Drug
    2003 Volume 122 Issue 2 Pages 141-150
    Published: 2003
    Released on J-STAGE: July 22, 2003
    JOURNAL FREE ACCESS
    Amrubicin is a completely synthetic anthracycline derivative. In contrast, however, the anthracyclines used clinically thus far have been produced by fermentation or semisynthesis. Amrubicin is structurally distinguishable from other anthracyclines by the amino group at the 9-position and its unique sugar moiety. Amrubicinol, the C-13 hydroxy- metabolite of amrubicin, is associated with a 5 to 200 times greater cytotoxicity than amrubicin. Amrubicin exhibited superior in vivo antitumor activity to doxorubicin in the human tumor xenograft model. Using this model, the level of amrubicinol (active metabolite) was shown to be higher than that of doxorubicin in tumor tissues, but lower in normal tissues. These results suggest potent therapeutic activity for amrubicin because of the selective distribution of its highly active metabolite, amrubicinol, in tumors. These anti-tumor effects of amrubicin are considered to be induced by DNA topoisomeraseII inhibition. In clinical studies, amrubicin has demonstrated potent single agent activity as compared to a standard regimen in untreated patients with extensive small cell lung cancer. Its major toxicity was myelosuppression (especially neutropenia).
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  • Kazuhito KAWABATA, Tetsuya HAGIO, Shozo MATSUOKA
    Article type: Review on New Drug
    2003 Volume 122 Issue 2 Pages 151-160
    Published: 2003
    Released on J-STAGE: July 22, 2003
    JOURNAL FREE ACCESS
    Imbalance between neutrophil elastase (NE) and its endogenous protease inhibitors has been considered to be one of possible mechanisms by which NE causes lung tissue destruction. It has been shown that the amount and/or activity of NE is increased in blood and bronchoalveolar lavage fluid in patients with acute lung injury. Accordingly, animals undergoing acute lung injury have increased NE activity such as in blood and bronchoalveolar lavage fluid. Sivelestat sodium hydrate (Sivelestat) is a synthetic inhibitor of NE with highly specificity to NE. Many studies have indicated that Sivelestat treatment improves inflammatory and edematous changes of lungs and survival as well as increased NE activity in several animal models of acute lung injury. Clinical studies have demonstrated that Sivelestat improves this injury that is associated with systemic inflammatory response syndrome. As compared with endogenous protease inhibitors that have high molecular mass, Sivelestat, a synthetic and low molecular weight elastase inhibitor, may be delivered to the inflammatory sites more easily and effectively and is considred to improve typical symptoms of acute lung injury. Clinical use of Sivelestat would further clarify the usefulness of this compound in clinical acute lung injury.
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  • Shinzaburo MINAMI, Rikizou HATTORI, Akira MATSUDA
    Article type: Review on New Drug
    2003 Volume 122 Issue 2 Pages 161-178
    Published: 2003
    Released on J-STAGE: July 22, 2003
    JOURNAL FREE ACCESS
    Pazufloxacin mesilate (PZFX: Pasil INJECTION, Pazucross INJECTION) is a novel injectable quinolone antibiotic that was discovered by Toyama Chemical Co., Ltd. and codeveloped by Toyama Chemical Co. Ltd. and Mitsubishi Pharma Corporation. Laboratory studies indicated that PZFX reached high plasma levels quickly after intravenous administration, and it exhibited weak convulsion inducing activity, low local irritant effect, and less hypotensive activity, all of which are generally recognized as side effects associated with other injectable quinolones. PZFX has potent antibacterial and bactericidal activities against cephalosporin-, carbapenem-, and aminoglycoside-resistant strains. These favorable antibacterial and bactericidal activities gave PZFX superior therapeutic effects, compared to injectable cephalosporin antibiotics, on experimental animal infection models caused by those resistant strains. Clinical studies also revealed PZFX was as safe and effective as the injectable cephalosporin, ceftazidime, against various moderate to severe infections. Furthermore, PZFX showed good clinical effects on the infections resistant to chemotherapy by the other antimicrobial agents. These results indicate that PZFX is a viable choice for various bacterial infections. In this review, results of laboratory and clinical studies are summarized and the clinical role of PZFX among the injectable antimicrobials is discussed.
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