Reperfusion diseases/injuries enzymes

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... 

The radical anion superoxide 02 is a product of activated leukocytes and endothelial cells and has been postulated to be a mediator of isch-emia-reperfusion injury and inflammatory and vascular diseases. Various superoxide dismutase (SOD) enzymes are known Cu,Zn-SOD in the cytoplasm of eukaryotic cells, Mn-SOD in mitochondria, and Fe-SOD and Mn-SOD in prokaryotic cells. They catalyze the conversion of 02 into H202 and 02... 

However, it is now recognised that neutrophils can contribute to host-tissue damage if they are activated to secrete reactive oxidants and granule enzymes, and if the local concentrations of anti-oxidants and protease inhibitors within the tissue are low or defective. Thus, inappropriate neutrophil activation leading to host-tissue damage has been implicated in reperfusion injury, Crohn s disease, adult respiratory distress syndrome (ARDS) and rheumatoid arthritis. In these conditions, it is envisaged that neutrophils accumulate in tissues and become inappropriately activated to secrete their cytotoxic products, which then initiate or contribute to host-tissue damage. 

Many pathological conditions, including ischemia/reperfusion, inflammation, and sepsis may induce tissues to simultaneously produce both superoxide and nitric oxide. For example, ischemia allows intracellular calcium to accumulate in endothelium (Fig. 20). If the tissue is reperfused, the readmission of oxygen will allow nitric oxide as well as superoxide to be produced (Beckman, 1990). For each 10-fold increase in the concentration of nitric oxide and superoxide, the rate of peroxynitrite formation will increase by 100-fold. Sepsis causes the induction of a second nitric oxide synthase in many tissues, which can produce a thousand times more nitric oxide than the normal levels of the constitutive enzyme (Moncada et al., 1991). Nitric oxide and indirectly peroxynitrite have been implicated in several important disease states. Blockade of nitric oxide synthesis with N-methyl or N-nitroarginine reduces glutamate-induced neuronal degeneration in primary cortical cultures (Dawson et al., 1991). Nitroarginine also decreases cortical infarct volume by 70% in mice subjected to middle cerebral artery occlusion (Nowicki et al., 1991). Myocardial injury from a combined hy-... 

Superoxide dismutases are a class of oxido-reductase enzymes which contain either Cu, Fe, or Mn at the active site and catalyze the dismutation of superoxide (1), the one-electron reduction product of molecular oxygen (Eqs. 1 and 2, where M" is the metalloenzyme in the reduced state and M" is the enzyme in the oxidized state) to oxygen and hydrogen peroxide. The SOD enzymes have been shown to have efficacy in animal models of disease states proposed to be, in part, mediated by superoxide, such as myocardial ischemia-reperfusion injury, " inflammation, and cerebral ischemia-reperfusion injury. Evidence for superoxide as a mediator... 

Our goal has been to develop the Mn(ii)-based SOD mimics shown in Figure 1 as therapeutic agents for diseases mediated by superoxide, particularly for the treatment of myocardial ischemia-reperfusion injury. We will discuss how the Mn(ii)-based SOD mimics were designed and illustrate the advantages of these SOD mimics over the SOD enzymes with regard to their SOD activity, stability, pharmacology and cost. 

The free radical superoxide, O2, reacts with nitric oxide, NO, to produce damaging peroxinitrite, OONO . This process has been postulated to be a mediator of ischemia-reperfusion injury as well as inflammatory and vascular diseases. Superoxide dismutases (SODs), enzymes discussed previously, are responsible for converting superoxide to hydrogen peroxide and oxygen. SODs are... 

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