Human diseases reperfusion injuries

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... 

As stated at the beginning of this article, the liver is the most intensively studied animal tissue in biochemistry. In the context of the role of free radicals in human diseases, the liver is not obviously at centre stage, since heart disease and cancer are more important in the industrialized world than, for example, cirrhosis. Free-radical biochemistry of the liver will remain a fertile area of work, however, not least because so many original ideas and techniques are developed there and then applied to the study of other tissues. The increasing use of liver transplantation, following the acceptance of kidney and heart transplants as almost routine, will surely increase the interest in the study of ischaemia-reperfusion injury in... 

Free radicals might be involved in the incidences of various diseases such as arthritis, hemorrhagic shock, atherosclerosis, advancing age, ischemia and reperfusion injury of many organs, Alzheimer and Parkinson s disease, gastrointestinal dysfunctions, tumor promotion and carcinogenesis, AIDS, and other human health problems [85]. The oxidative proanthocyanidins as antioxidants could quench the free radicals and might help to enhance the action of other antioxidants such as vitamin C. 

Recent researches have indicated that lipid peroxidation is involved in the pathogenesis of other human diseases such as hypoxic-ischemic reperfusion injury, cancers, Alzheimer s disease, rheumatoid arthritis, renal dysfunction, and diabetes mellitus. 

Alterations in the amounts of Bcl-2 proteins have been associated with diseases in which too much or too little cell death occurs (this is referred to as cell loss and cell accumulation, respectively). These diseases include cancer, autoimmune disorders such as lupus, immunodeficiency associated with human immunodeficiency virus (HIV) infection, and ischemia-reperfusion injury during stroke and myocardial infarction, among others [31]. 

Figure 4 shows the allometric plots of pharmacokinetic parameters for the recombinant, soluble, and chimeric form of P-selectin glycoprotein ligand-1 (rPSGL-Ig), an antagonist to P-selectin for the treatment of P-selectin-mediated diseases like thrombosis, reperfusion injury, and deep vein thrombosis. Human rPSGL-Ig pharmacokinetic parameters could accurately be predicted on the basis of data from mouse, rat, monkey, and pig using allometric power functions [54]. 

Resolvins (Rv) are derivatives of EPA and/or DHA and are now well-established as exhibiting anti-inflammatory or pro-resolving properties. They were first identi-hed in a murine air pouch model by Serhan in 2000 (Serhan et al. 2000), and since then have been both applied and detected in various animal inflammatory disease models (i.e., colitis, ischemia-reperfusion injury, wound healing) and human nutritional intervention/disease studies (Kasuga et al. 2008 Bento et al. 2011 Norling et al. 2011 Giera et al. 2012 Mas et al. 2012). 

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