Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Patent
1996-12-16
1999-07-27
Kishore, Gollamudi S.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
436 71, 436501, 436811, A61K 748
Patent
active
059286245
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to compositions and methods for neutralizing lipopolysaccharide, and treatment of gram-negative sepsis based thereon.
BACKGROUND OF THE INVENTION
Sepsis is morbid condition frequently induced by a toxin, the introduction or accumulation of which is most commonly caused by infection or trauma. The initial symptoms of sepsis or septic shock typically include chills, profuse sweat, irregularly remittent fever, prostration and the like, followed by persistent fever, hypotension leading to shock, neutropenia, leukopenia, disseminated intravascular coagulation, adult respiratory distress syndrome and multiple organ failure. These final symptoms, generally referred to as acute phase septic shock, almost invariably lead to death.
Sepsis-inducing toxins have been found associated with pathogenic bacteria, viruses, plants and venoms. Among the well described bacterial toxins are the endotoxins or lipopolysaccharides (LPS) of the gram-negative bacteria. These molecules are glycolipids that are ubiquitous in the outer membrane of all gram-negative bacteria. While the chemical structure of most of the LPS molecule is complex and diverse, a common feature is the lipid A region of LPS (Rietschel et al., 1984, In Handbook of Endotoxins, eds. R. A. Proctor and E. Th. Rietschel, Elsevier, Amsterdam 1:187-214). Recognition of lipid A in biologic systems initiates many, if not all, of the pathophysiologic changes of sepsis. Because lipid A structure is highly conserved among all types of gram-negative organisms, common pathophysiologic changes characterize gram-negative sepsis.
Current concepts support the contention that the primary response of the host (including man) to LPS involves the recognition of LPS by cells of the monocyte/macrophage lineage, followed by the rapid elaboration of a variety of cell products including the general group known as cytokines. Other cell types believed to participate in sepsis and in particular in the response to LPS are polymorphonuclear leukocytes and endothelial cells; each of these cell types are also capable of responding to LPS with the elaboration of potent inflammatory substances.
LPS is believed to be a primary cause of death in humans during gram-negative sepsis, particularly when the symptoms include adult respiratory distress syndrome (ARDS) (van Deventeret al., 1988, Lancet, 1:605: Ziegler et al., 1987, J. Infect. Dis. 136:19-28). For instance, one particular cytokine, tumor necrosis factor alpha/cachectin (TNF), has been reported to be a primary mediator of septic shock (Beutler et al., 1987, N. Eng. J. Med. 316:379). Intravenous injection of LPS endotoxin from bacteria into experimental animals and man produces a rapid, transient release of TNF (Beutler et al., 1985, J. Immunol. 135:3972; Mathison et al., 1988, J. Clin. Invest. 81:1925). Evidence that TNF is a critical mediator of septic shock comes primarily from experiments in which pretreatment of animals with anti-TNF antibodies reduces lethality (Beutler et al., 1985, Science 229:869; Mathison et al., supra). These reports suggest that interruption of the secretion of TNF caused by LPS or other factors would ameliorate the often lethal symptoms of sepsis.
Upon introduction of LPS into the blood, it may bind to a protein termed lipopolysaccharide binding protein (LBP). LBP is a 60 kD glycoprotein present at concentrations of less than about 5 .mu.g/ml in the serum of healthy animals and man. During the acute phase, LBP is synthesized by hepatocytes, and reaches concentrations of 30-50 .mu.g/ml in serum. LBP can be purified from acute phase human and rabbit serum (Tobias et al., 1986, J. Exp. Med. 164:777-793). LBP recognizes the lipid A region of LPS and forms complexes with both rough and smooth form LPS (Tobias et al., 1989, J. Biol. Chem. 264:10867-10871). LBP bears N-terminal sequence homology with the LPS-binding protein known as bactericidal permeability-increasing factor, (BPI) (Tobias et al., 1988, J. Biol. Chem. 263:13479-13481). BPI is stored in the specif
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Hailman Peter Eric
Wright Samuel D.
Wurfel Mark M.
Kishore Gollamudi S.
The Rockefeller University
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