LEX-032

Reperfusion injury is defined as the enhancement of the damage that occurs in ischaemic cells during the reperfusion period. Cellular damage to the brain occurs not only during the ischaemic period, but also during the reperfusion period. Such injury occurs when blood flow is restored to heart, brain or other tissue after flow has been blocked. Several mechanisms appear to play a role in the generation of reperfusion injury. To a greater or lesser extent, most involve neutrophils. The infiltration of neutrophils into the previously ischaemic area has been implicated as playing major role following reperfusion. Microscopic examination of tissue has shown a direct correlation between the duration of oxygen deprivation with the amount of damage, and the extent of activated neutrophil recruitment. Activated neutrophils are responsible for the release of serine proteases, which directly lead to tissue damage. Activated neutrophils also contain a newly assembled enzyme that produces tissue damaging free radicals. However, a preliminary and necessary step is to attach the activated neutrophil on to the lining of the blood vessels, a process requiring proteolytic activity. Administration of a drug that prevents neutrophil transmigration would reduce reperfusion injury. SuperGen is developing a drug, LEX 032, with a unique spectrum of activities, including the ability to inhibit binding of neutrophils to the vascular surface by blocking this proteolytic activity. In addition, this drug inhibits free radical production by neutrophils, and inhibits the activity of released serine proteases. Therefore, LEX 032 is expected to prevent or minimise neutrophil mediated reperfusion injury. Blockade of all three destructive inflammatory responses should limit the amount of damaged tissue and save viable tissue. A drug with these capabilities might find use in the treatment of myocardial infarction, shock-resuscitation, replantation surgery, frostbite, burns and organ transplantation. Since LEX 032 has no inhibitory activity against thrombin and plasmin, it represents an ideal drug for use in the treatment of ischaemic stroke. Recently, data have been published demonstrating that ischaemic stroke patients given the thrombolytic drug tPA were at least 30% more likely to have minimal or no disability at three months, as measured by outcome scales, when compared to placebo-treated patients. Presumably, this action was because of the hastening of brain reperfusion, and may have been limited due to reperfusion injury. The FDA approved the use of tPA for the limited treatment of acute ischaemic stroke. Since LEX 032 has been shown to limit neutrophil mediated reperfusion damage, it may find use either alone, to ameliorate damage occurring spontaneously during ischaemic stroke, or in combination therapy with tPA to reduce reperfusion injury secondary to thrombolytic therapy. This unique approach may have broad therapeutic potential in the treatment of neutrophil mediated diseases since, unlike a monoclonal antibody for example, it is independent of the specific adhesion molecule(s). These diseases include inflammatory diseases which are, at least in part, caused or exacerbated by excessive neutrophil proteases, such as acute pancreatitis, arthritis, allograft rejection, sepsis, meningitis, acute pulmonary inflammation, psoriasis and damage caused by burns. This is in addition to reperfusion-related diseases such as myocardial infarction, stroke, shock-resuscitation, replantation surgery, frostbite, burns and organ transplantation.

Because neutrophil proteinases such as elastase and cathepsin G are considered to play a major role in inflammatory tissue damage, the microcirculatory effect of the serine proteinase inhibitor (serpin) Lex032 after ischemia/reperfusion (I/R)-induced pancreatitis was investigated. Lex032 inhibits these proteinases by recombinant combination of alpha(1)-antitrypsin and alpha(1)-antichymotrypsin. Twenty-eight anesthetized rats received either Lex032 or NaCl 0.9% as a control solution during baseline conditions or after 1 h of complete reversible ischemia induced by microclip occlusion of the pancreatic arteries. The number of erythrocyte-perfused capillaries (functional capillary density) and the leukocyte adherence in postcapillary venules were assessed by intravital microscopy 45, 90, and 120 min after administration. In the baseline group, Lex032 increased leukocyte adherence compared with the NaCl 0.9% baseline group, without changing any other parameter. I/R without Lex-032 treatment resulted in a 50% reduction in functional capillary density, a 2-fold increase in leukocyte adherence, an increase in interleukin-6 serum concentration, and a significant fall in blood pressure during reperfusion time compared with baseline animals. Treatment with Lex032 in I/R resulted in significant preservation of capillary perfusion, an absence of interleukin-6 increase, and preservation of mean arterial pressure during reperfusion time, without changing the leukocyte adherence, compared with the NaCl 0.9% I/R group. Because of its considerable amelioration of microcirculatory perfusion, Lex032 might be useful in the treatment of pancreatic I/R tissue damage (e.g., cardiac bypass surgery, pancreas transplantation, and hemorrhagic shock) by prevention of capillary perfusion failure.