Ischemia reperfusion injury

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

Kim, M.-S. and Akera, T. (1987). O2 free radicals cause of ischemia-reperfusion injury to cardiac Na -K ATPase. Am. J. Physiol. 21, H252-H257. 

Sakomoto, A., Ohnishi, S.T., Ohnishi, T. and Ogawa, R. (1991). Relationship between free radical production and lipid peroxidation during ischemia-reperfusion injury in the rat brain. Brain Res. 554, 186-192. 

Belperio JA, Keane MP, Burdick MD, et al. CXCR2/CXCR2 ligand biology during lung transplant ischemia-reperfusion injury. J Immunol 2005 175 6931-6939. 

Boyle EM, Jr., Kovacich JC, Hebert CA, et al. Inhibition of interleukin-8 blocks myocardial ischemia-reperfusion injury. J Thorac Cardiovasc Surg 1998 116(1) 114-121. 

Soriano SG, Amaravadi LS, Wang YF, et al. Mice deficient in fractalkine are less susceptible to cerebral ischemia-reperfusion injury. J Neuroimmunol 2002 125 59-65. 

Ischemia-reperfusion is thought to mediate the severe organ dysfunction witnessed after shock or cardiac arrest. HSPs could play a major role in the defence against ischemia-reperfusion injury. Many in vivo experimental models of ischemia and/or ischemia-reperfusion have demonstrated HSP induction. 

Kusterer K, Bojunga J, Enghofer M, Heidenthal E, Usadel KH, Kolb H, Martin S. Soluble ICAM-1 reduces leukocyte adhesion to vascular endothelium in ischemia-reperfusion injury in mice. Am J Physiol 1998 275 G377-380. 

The regulation of superoxide formation by SOD can affect both in vivo and ex vivo lipid peroxidation. Thus, SOD inhibited lipid peroxidation in cats following regional intestinal ischemia and reperfusion [33], Similarly, the treatment of rats with polyethylene glycol superoxide dismutase (PEG-SOD) prevented the development of lipid peroxidation in hepatic ischemia-reperfusion injury [34], Interesting data have been reported by Bartoli et al. [35]. They showed that SOD depletion in the liver of rats feeding with a copper-deficient diet... 

Later on, the importance of xanthine oxidase as the producer of reoxygenation injury was questioned at least in the cells with low or no xanthine oxidase activity. Thus, it has been shown that human and rabbit hearts, which possess extremely low xanthine oxidase activity, nonetheless, develop myocardial infractions and ischemia-reperfusion injury [9], However, recent studies supported the importance of the xanthine oxidase-catalyzed oxygen radical generation. It has been showed that xanthine oxidase is partly responsible for reoxygenation injury in bovine pulmonary artery endothelial cells [10], human umbilical vein and lymphoblastic leukemia cells [11], and cerebral endothelial cells [12], Zwang et al. [11] concluded that xanthine dehydrogenase may catalyze superoxide formation without conversion to xanthine oxidase using NADH instead of xanthine as a substrate. 

Mitochondria, nitric oxide synthase and arachidonic acid metabolism are sources of reactive oxygen species during ischemia—reperfusion injury 568... 

Nitric oxide and peroxynitrite contribute to oxidative damage 569 Production of eicosanoids from polyunsaturated fatty acids such as arachidonic acid may generate reactive oxygen species 570 Brain antioxidant defenses modify ischemia-reperfusion injury 570 Reactive oxygen species may modify both the excitotoxic and the apoptotic components of ischemic brain damage 570... 

Mitochondria, nitric oxide synthase and arachidonic acid metabolism are sources of reactive oxygen species during ischemia-reperfusion injury. ROS generation during ischemia-reperfusion may come from several sources, including NOS activity, mitochondrial electron transport, multiple steps in the metabolism of arachidonic... 

Brain antioxidant defenses modify ischemia-reperfusion injury. The high metabolic rate ofbrain cells implies a high baseline ROS production, and brain cells possess high concentrations of both enzymatic and small-molecule antioxidant defenses. SOD1 may represent as much as 1% of total protein in brain it converts 02 to H202, which is then further metabolized to water and oxygen by... 

Rieger JM, Shah AR, Gidday JM (2002) Ischemia-reperfusion injury of retinal endothelium by cyclooxygenase- and xanthine oxidase-derived superoxide. Exp. Eye Res. 74 493-501. 

Zingarelli B, Salzman AL, Szabo C (1998) Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury. Circ Res 83 85-94... 

Recently, monoclonal antibodies were attached to gas-filled microbubbles using this spacer coupHng technology. Testing in vitro, in a cell culture system, demonstrated selective accumulation of decafluorobutane-based lipid shell MP1950 microbubbles with covalently attached anti-lCAM-1 antibodies, onto the surface of activated endotheUum [8]. Anti-P-selectin antibodies attached to such microbubbles via an avidin-biotin scheme showed selective accumulation in the areas of inflammation and ischemia/reperfusion injury in an animal model [93]. In the latter example, biotin was also connected to the microbubble surface via a flexible polymer spacer arm. 

Basically, the intravenous application of micronutrients can also be classified as nutritargeting. Specifically, when target tissues like the endothelium of the vessels must be supplied with a higher dose of vitamin E to ensure good protection during surgery with ischemia/reperfusion injury, the parenteral route is superior over the "controlled" oral route (Bartels et al, 2004). 

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