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Pyruvate thiolester for the prevention of reperfusion injury (Text)

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  • Background of the invention: This invention relates to a new pyruvate compound and a method of treating ischemia in mammalian hearts, lungs, veins, arteries and other organs or tissues. The invention is particularly directed to a method of treating an organ depleted of oxygen with a therapeutic amount of the novel pyruvate compound. The inventive method is especially effective in treating cardiac ischemia and in increasing the viability of transplanted organs. Description: Ischemia is defined herein as the interruption of oxygen supply, via the blood, to an organ or to part of an organ. Examples of ischemic events include (i) myocardial, cerebral, or intestinal infarction following obstruction of a branch of a coronary, cerebral, or mesenteric artery, and (ii) removal and storage of an organ prior to transplantation. In the case of myocardial infarction, prompt restoration of blood flow to the ischemic myocardium, i.e. coronary reperfusion, is a key component of the treatment. This is because mortality is directly related to infarct size (tissue necrosed) which is related to the severity and duration of the ischemic event. Notwithstanding the need to supply an organ cut-off from a normal blood supply with oxygen, it has been found that reperfusion injury may occur upon restoration of blood flow. This results from the production of reactive oxygen species (ROS), namely, hydrogen peroxide, hydroxyl radicals and superoxide radicals which are formed from both extracellular and intracellular sources. Particularly, ROS are highly reactive species that, under normal conditions, are scavenged by endogenous defense mechanisms. However, under conditions of post-ischemic oxidative stress, ROS interact with a variety of cellular components, causing peroxidation of lipids, denaturation of proteins, and interstitial matrix damage, resulting in increase of membrane permeability and release of tissue enzymes. In an attempt to minimize these undesirable side effects of perfusion, researchers Simpson, et al., (Free Radical Scavengers and Myocardial Ischemia, Federation Proceedings, Volume 46, No. 7 May 15, 1987) suggest the use of an inhibitor of ROS production to protect the reperfused myocardium. Particularly, the Simpson, et al. disclosure is directed to the use of agents and inhibitors (ex. allopurinol) that reduce ROS levels. In a similar context, Brunet, et al., (Effects of Acetylcysteine, Free Radical Biology and Medicine, Volume XX, No. X 1995) suggest the use of acetylcysteine to reperfuse hearts. In particular, the article concludes that acetylcysteine treatment decreases the production of ROS in reperfused rat hearts. In a further effort directed to protecting reperfused heart tissue, U.S. Pat. No. 5,075,210, herein incorporated by reference, discloses a process for reperfusing a heart for transplantation.
  • 1997-09-16
  • Delphion Inc.,
  • English
  • text
  • text/pdf
  • ksl:casepat-us5667962
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Case Western Reserve University Patents