Author: Katagiri, Hiroyuki ; Narumiya, Shuh ; Majima, Masataka ; Ishii, Ken-ichiro ; Ito, Yoshiya ; Murata, Takahiko ; Suematsu, Makoto ; Yamashina, Shohei ; Hayashi, Izumi ; Kakita, Akira

Although thromboxanes (TXs), whose synthesis is regulated by cyclooxygenase (COX), have been suggested to promote inflammation in the liver, little is known about the role of TXA2 in leukocyte endothelial interaction during endotoxemia. The present study was conducted to investigate the role of TXA2 as well as that of COX in lipopolysaccharide (LPS)-induced hepatic microcirculatory dysfunction in male C57Bl/6 mice. We observed during in vivo fluorescence microscopic study that LPS caused significant accumulation of leukocytes adhering to the hepatic microvessels and non-perfused sinusoids. Levels of serum alanine transaminase (ALT) and tumor necrosis factor alpha (TNFα) also increased. LPS raised the TXB2 level in the perfusate from isolated perfused liver. A TXA2 synthase inhibitor, OKY-046, and a TXA2 receptor antagonist, S-1452, reduced LPS-induced hepatic microcirculatory dysfunction by inhibiting TNFα production. OKY-046 suppressed the expression of an intercellular adhesion molecule (ICAM)-1 in an LPS-treated liver. In thromboxane prostanoid receptor-knockout mice, hepatic responses to LPS were minimized in comparison with those in their wild-type counterparts. In addition, a selective COX-1 inhibitor, SC-560, a selective COX-2 inhibitor, NS-398, and indomethacin significantly attenuated hepatic responses to LPS including microcirculatory dysfunction and release of ALT and TNFα. The effects of the COX inhibitors on hepatic responses to LPS exhibited results similar to those obtained with TXA2 synthase inhibitor, and TXA2 receptor antagonist. In conclusion, these results suggest that TXA2 is involved in LPS-induced hepatic microcirculatory dysfunction partly through the release of TNFα, and that TXA2 derived from COX-1 and COX-2 could be responsible for the microcirculatory dysfunction during endotoxemia. (Hepatology 2004;39:139-150.)

01 Jan 2003·European Surgical ResearchQ4 · MEDICINE

Effects of Selective Cyclooxygenase Inhibitors on Ischemia/Reperfusion-Induced Hepatic Microcirculatory Dysfunction in Mice

Q4 · MEDICINE

Article

Author: Ito, Y. ; Hayashi, I. ; Kakita, A. ; Majima, M. ; Katagiri, H. ; Ishii, K.

We examined the effects of selective cyclooxygenase (COX) inhibition on hepatic warm ischemia/reperfusion (I/R) injury in mice. A selective COX-1 inhibitor, SC-560, selective COX-2 inhibitors, NS-398 and celecoxib, and indomethacin were administered 30 min before ischemia. Four hours after reperfusion, an in vivo microscopic study showed that I/R caused significant accumulation of leukocytes adhering to the hepatic microvessels and nonperfused sinusoids. Levels of plasma alanine transaminase (ALT) and tumor necrosis factor (TNF)-α also showed increases. SC-560, NS-398, celecoxib and indomethacin significantly reduced hepatic responses to I/R including microcirculatory dysfunction and release of ALT and TNF-α. Moreover, the effects of the thromboxane (TX) A2 (TXA2) synthase inhibitor OKY-046 and the TXA2 receptor antagonist S-1452 on hepatic responses to I/R exhibited results similar to those obtained with COX inhibitors. These results suggest that COX-1 and COX-2 contribute to I/R-induced hepatic microvascular and hepatocellular injury partly through TNF-α production, and that TXs derived from COX are partly responsible for I/R-induced liver injury.

01 Jan 2003·Drug Metabolism and PharmacokineticsQ4 · MEDICINE

Separate Assessment of Intestinal and Hepatic First-pass Effects Using a Rat Model with Double Cannulation of the Portal and Jugular Veins

Q4 · MEDICINE

Article

Author: Noboru Okamura ; Tsuyoshi Murakami ; Takeo Yoshimori ; Ryo Norikura ; Machiko Nakanishi ; Kenji Mizojiri

To separately assess intestinal and hepatic first-pass effects with absorption ratio data, we have established an experimental model of rats double-cannulated into the portal and jugular veins. The model allows us to take blood samples simultaneously from conscious rats that have recovered from surgical damage. Double cannulation did not alter the physiological and hematological conditions. Moreover, the plasma concentration profiles of unchanged drug following oral and intravenous administration in the double-cannulated rats were not different from those of rats single-cannulated into the jugular vein. These results suggest that the model can be useful for separately assessing intestinal and hepatic first-pass effects. We evaluated the first-pass effects in the intestine and the liver separately using this model. S-1452, as a model drug with 94% absorption ratio, was administered intravenously and orally to the double-cannulated rats, and the drug concentrations in the portal and systemic plasma were determined, and the rates of elimination from the intestine and liver were estimated. In the first pass, approximately 26% and 56% of the dose were extracted by the intestine and liver, respectively. This method, in which the animal is not restricted nor under anesthesia, allows us to obtain reliable values of individual first pass effects in the intestine and liver. This method can also be an effective tool for assessing the site and extent of drug-drug interaction on the first-pass effects.

100 Deals associated with Domitroban

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	NDA/BLA	JP	Shionogi & Co., Ltd.	-
Intracranial Thrombosis	NDA/BLA	JP	Shionogi & Co., Ltd.	-
Rhinitis, Allergic	NDA/BLA	JP	Shionogi & Co., Ltd.	-
Thromboembolism	NDA/BLA	-	Shionogi & Co., Ltd.	-
Thrombosis	NDA/BLA	-	Shionogi & Co., Ltd.	-

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