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RESEARCH OF THE MECHANISM OF MULTIPLE ORGAN FAILURE ASSOCIATED WITH SEPSIS-IN ASSOCIATION WITH APOPTOSIS

Research Project

Project/Area Number 11671517
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Anesthesiology/Resuscitation studies
Research InstitutionOSAKA CITY UNIVERSITY

Principal Investigator

ASADA Akira (2000-2001)  OSAKA CITY UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, ANESTHESIOLOGY AND INTENSIVE CARE MEDICINE, PROFESSOR, 大学院・医学研究科, 教授 (00047367)

小田 裕 (1999)  大阪市立大学, 医学部, 講師 (70214145)

Co-Investigator(Kenkyū-buntansha) ODA Yutaka  OSAKA CITY UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, ANESTHESIOLOGY AND INTENSIVE CARE MEDICINE, LECTURER, 大学院・医学研究科, 講師 (70214145)
TANAKA Kazuo  OSAKA CITY UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, ANESTHESIOLOGY AND INTENSIVE CARE MEDICINE, RESEARCH ASSOCIATE, 大学院・医学研究科, 助手 (90285297)
浅田 章  大阪市立大学, 医学部, 教授 (00047367)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsPROPOFOL / MIDAZOLAM / CYTOCHROME P450 / P4502B6 / P4503A4 / mRNA / APOPTOSIS / チトクローム8450 / 敗血症 / cytochrome P450 / RT-RCR / RT-PCR / チトクローム P450 / CYP2E1 / CYP3A4
Research Abstract

Research in 1999 and 2000 : Pharmacokinetics of various drugs is affected by the development of sepsis, Propofol is an intravenous anesthetic used for sedation in patients with sepsis. To elucidate the alternation of pharmacokinetics of anesthetics by sepsis, we have elucidated the hepatic enzymes involved in the metabolism of propofol. We have shown that cytochrome P4502B6, not P4502C as previously reported, is the predominant P450 isoform involved in the metabolism of propofol using human liver microsomes, cDNA-expressed microsomes and monoclonal antibodies. Secondly, involvement of P4502B6 and P4502C in the metabolism of midazolam was examined since the pharmacokinetics of midazolam is inhibited by propofol, which was metabolized by P4502B6. Although the metabolism of midazolam was competitively inhibited by propofol both in vitro and in vivo, only P4503A4 was involved in the metabolism of midazolam to 1 '-hydroxy midazolam and P4502B6 or P4502C were not involved.
Research in 2001 : To elucidate the pharmacokinetics of intravenous anesthetics in various conditions, we have established an animal model with Sprague-Dawley rats. This is an awake rat model with intraarterial and intravenous catheters, which enables to observe the effect of anesthetics with monitoring arterial pressure, blood gas tension. Sepsis model can be easily made by injecting lipopolysaccharide to this rat.
Future plan : To elucidate the effect of sepsis on the levels of P4503A4mRNA in lymphocytes in peripheral blood, hepatic P4503A4 activity and apoptosis of the hepatic cells. The level of P4503A4mRNA in lymphocytes in peripheral blood is correlated with the P4503A4 activity in the liver. By comparing the level of P4503A4mRNA in lymphocytes in peripheral blood and the P4503A4 activity in the liver with the development of sepsis, we can detect whether apoptosis in the liver is induced by alteration in the P450 levels in the liver or P450 in the peripheral blood.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (35 results)

All Other

All Publications (35 results)

  • [Publications] Y.Oda: "Fontanyl inhibits the metabolism of midazolam: competitive inhibition of CYP3A4 in vitro"British Journal of Anaesthesia. 82. 900-903 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] N.Hamaoka: "Propofol decreases the clearance of midazolam by inhibiting CYP3A4: An in vivo and in vitro study"Clinical Pharmacology and Therapeutics. 66. 110-117 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] T.Nakamoto: "Quantitative RT-PCR for CYP3A4 mRNA in human periphoral lymphocytes: Induction or CYP3A4 in lymphooytes and in liver by rifampioin"Pharmacogenetics. 10. 571-575 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] I.Hase: "Area under the plasma concentration-times ourve of inorganic fluorlde following sevoflurance anesthesia correlates with CYP2E1 mRNA level in mononuclear cells"Anesthesiology. 92. 1661-1666 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Y.Oda: "Involvement of human liver cytcchrome P4502B6 in the metabolism of propofol"British Journal of Clinical Pharmacology. 51. 281-285 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Y.Oda: "Metabolism of levo-α-acetylmethadol (LAAM) by human liver cytochrome P450: Involvement of CYP3A4 characterized by atypical kinetics with two binding sites"Journal of Pharmacology and Experimental Therapeutics. 297. 410-422 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 小田 裕: "平成12年度基礎麻酔セミナー「薬物動態:基礎研究から臨床応用まで」"真興交易医書出版部. 100-120 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Y. Oda: "Fentanyl inhibits the metabolism of midazolam : competitive inhibition of CYP3A4 in vitro"Br. J, Anaesth. 82. 900-903 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] N. Hamaoka: "Propofol decreases the olearance of midazolam by inhibiting CYP3A4 : An in vivo and in vitro study"Clin, Pharmacol, Ther. 66. 110-117 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K. Mizutani: "Preoperative epidural morphine using double-catheter technique for esophagectomy"Osaka City Medical Journal. 45. 129-138 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] T. Nakamoto: "Quantitative RT-PCR for CYP3A4 mRNA in human peripheral lymphocytes : Induction of CYP3A4 in lymphocytes and in liver by rifampicin"Pharmacogenetics. 10. 571-575 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] I. Hase: "Area under the plasma concentration-time curve of inorganic fluoride following sevoflurane anesthesia correlates with CYP2E1 mRNA level in mononuclear cells"Anesthesiology. 92. 1661-1666 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Y. Oda: "Involvement of human liver cytochrome P4502B6 in the metabolism of propofol"Br, J, Clin, Pharmacol. 51. 281-285 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] N. Hamaoka: "Cytochrome P4502B6 and 2C9 do not metabolize midazolam : kinetic analysis and inhibition study with monoclonal antibodies"Br. J. Anaesth. 86. 850-854 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Y. Oda: "Metabolism of levo-α-acetylmethadol (LAAM) by human liver cytochrome P450 : Involvement of CYP3A4 characterized by atypical kinetics with two binding sites"J, Pharmacol. Exp. Ther. 297. 410-422 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Y. Oda: "Metabolism of methadone and levo-α-acetylmethadol (LAAM) by human intestinal P4503A4 (CYP3A4) : Potential contribution of intestinal metabolism to pre-systemic clearance and bioactivation"J. Pharmacol. Exp. Ther. 298. 1021-1032 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Y. Oda: "Drug metabolism : from basic research to clinical application"Journal of Clinical Anesthesia (Japan). 400

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tsuchiya M.: "Antloridant protection of propofol and its recycling in erythrocyte membranes"Am J Resp Crit Care Med. 165(1). 54-60 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsuchiya M.: "Propofol versus midazolam regarding their antioxidant activities"Am J Resp Crit Care Med. 163(1). 26-31 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Iida Y.: "Effect of mild therapeutic hypothermia on phenytoin pharmacohinetics"Ther Drug Munit. 23(3). 192-197 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hamaoka N.: "Cytochrome 2B6 and 2C9 do not metabolize midazolam: kinetic analysis and inhibition study with monoclonal antibodies"Br J Anaesth. 86(4). 540-544 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Mori T.: "Modulation of neuronal nicotinic acetylcholine receptors by halothane in rat cortical neurons"Mol Pharmacol. 59(4). 732-743 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Oda Y.: "Metabolism of levo-α-acetylmethadol (LAAM) by human liver cytochrome P450: Involvement of CYP3A4 characterized by atypical kinetics with two binding sites"J Pharmacol Exp Ther. 297(1). 410-422 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yutaha Oda, et al: "Fentanyl inhibits metabolism of midazolam : competitive inbibition of CYP3A4 in ritro."British Journal of Anaesthesia. 82・6. 900-903 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Naoya Hamaoha, et al: "Propofol decreases the clearance of midazolam by inhibiting CYP3A6 : An inviro and in vitro study."Clinical Pharmacology and Therapeutics. 66・2. 110-117 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ichiro Hare, et al: "Area under the plasma concentration-time carre of inaganic fluoride following seroflurane anesthesia correlates with CYP2EImRNA level in menoroderal"Anesthesiology. 92・6. 1661-1666 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nahamoto, T, et al: "Quantitative RT-PCR for CYP3APmPNA in peripleral lymphocytes : Induction of CYP3A4 in lymphetytes and in liver by rifampicm"Pharamcogenetics. 10. 571-575 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takashi Mori et al.: "Basis of variable sensitivities of GABA_A receptors to ethanal"Alcohol Clin Exp Res. 24・7. 965-971 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yutaka Oda, et al: "Involvement human liver cytochrome P4502B6 in the metabolism of propofol"Br J Clin Pharmacol. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 小田裕,浅田章: "臨床麻酔臨時増刊"真興交易医書出版部. 15 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Osa Y, et al: "Fentanyl inhibits metabolism of midazolam : competitive inhibition of CYP3A4 in vitro"British Journal of Anaesthesia. 82・6. 900-903 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hamaoka N, et al: "Propofol decieases the clearance of midazo lam by inhibiting (YP3A4 : An in vivo and in vitro study"Clinical Pharmacology and Therapeutics. 66・2. 110-117 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hase I, et al: "Plasma fluoride AUC following seroflurane anesthesia correlates with (YP2E1 mRNA level in manon*clear cell"Anesthesiology. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Nakamoto T, et al: "Quantitative RT-PCR for CYP3A4 mRNA in human peripheral lymphocytes"Pharmacogenetics. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] 小田 裕,浅田 章: "臨床麻酔別冊 平成11年度 基礎麻酔セミナー"真興交易医書出版部(印刷中). (2000)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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