Ischemia-reperfusion

Kanashiro, M., Matsubara, T., Goto, T., and Sakamoto, N. (1993). Cyprid-ina luciferin analog reduces the incidence of ischemia/reperfusion-induced ventricular fibrillation. Jpn. J. Pharmacol. 63 47-52. 

Ischemia-reperfusion damage Stroke (A,l), cardiac failure (A), transplantation (A)... 

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... 

Acute over-activation of NHE1 results in a marked elevation in intracellular sodium concentration with a subsequent increase in intracellular calcium, via the Na +/Ca++ exchanger. This in turn triggers a cascade of injurious events that can culminate in tissue dysfunction and ultimately apoptosis and necrosis. This is commonly seen in organs such as the heart, brain and kidneys as a consequence of ischemia-reperfusion. 

The potency of the inhibitors is affected by the pH. Changes in pH affect the protonation state of the guanidine. In conditions of low pH, such as in ischemia-reperfusion, some dtugs such as cariporide work more efficiently because they are on average more positively charged. 

Urata H, Kinoshita A, Misono KS, Bumpus FM. Husain A Identification of a highly specific chy-mase as the major angiotensin Il-forming enzyme in the human heart. J Biol Chem 1990 265 22348. Silver RB, Reid AC, Mackins CJ, Askwith T, Schaefer U, Herzlinger D, Levi R Mast cells a unique source of renin. Proc Natl Acad Sci USA 2004 101 13607. Mackins CJ, Kano S, Sevedi N, Schafer U, Reid AC, Machida T, Silver RB, Levi R Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion. J Clin Invest 2006 116 1063. 

FIGURE 5.5 (a) Comparison of ischemia-reperfusion profiles in various control and NBO... 

Singhal AB, Wang X, Sumii T, Mori T, Lo EH. Effects of normobaric h3fperoxia in a rat model of focal cerebral ischemia-reperfusion. J Cereb Blood Flow Metab 2002 22 861 868. 

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. 

Oliver, C.N., Starke-Reed, P.E., Stadtman, E.R., Liu, G.J., Carney, J.M. and Floyd, R.A. (1990). Oxidative damage to brain proteins, loss of glutamine synthetase activity, and production of free radicals during ischemia/reperfusion-induced injury to gerbil brain. Proc. Natl Acad. Sd. USA 87, 5144-5147. 

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. 

Ayene, I.S., Al-Mchdi, A.B. and Fisher, A.B. (1993). Inhibition of lung tissue oxidation during ischemia/reperfusion by 2-mercaptopropionylglycine. Arch. Biochem. Biophys. 303, 307-312. 

Cugini D, Azzollini N, Gagliardini E, et al. Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to ischemia/reperfusion. Kidney Int 2005 67 1753-1761. 

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. 

Heat shock proteins (HSPs) are synthesized by cells in response to an increase in temperature, as well to various other stressful stimuli. Their main function is to ensure intracellular protein homeostasis, thus preserving the cells viability in the presence of aggression. Current evidence points to a protective role for HSPs in several aspects of critical disease, such as ischemia-reperfusion, ARDS, and multiple organ failure. The increase of a few degrees Celsius above the normal environmental temperature of cells leads to the heat shock response 1) rapid expression of heat shock genes, 2) suppression of normal protein synthesis, and 3) the ability of cells to survive a second and otherwise lethal heat challenge (thermotolerance). 

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. 

Lauver DA, Lockwood SF, and Lucchesi BR. 2005. Disodium disuccinate astaxanthin (Cardax) attenuates complement activation and reduces myocardial injury following ischemia/reperfusion. Journal of Pharmacology and Experimental Therapeutics 314(2) 686-692. 

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. 

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