Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-10-12
2004-02-03
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S021800, C514S838000, C514S893000, C514S894000, C530S324000, C530S350000, C530S829000, C424S529000, C424S534000
Reexamination Certificate
active
06686332
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to therapeutic uses of bactericidal/permeability-increasing (BPI) protein products for the treatment of adverse effects associated with depressed reticuloendothelial system function generally and specifically for treatment of adverse effects associated with impaired liver function resulting from physical, chemical or biological insult to the liver.
BPI is a protein isolated from the granules of mammalian polymorphonuclear leukocytes (PMNs or neutrophils), which are blood cells essential in the defense against invading microorganisms. Human BPI protein has been isolated from PMNs by acid extraction combined with either ion exchange chromatography [Elsbach,
J. Biol. Chem.,
254:11000 (1979)] or
E. coli
affinity chromatography [Weiss, et al.,
Blood,
69:652 (1987)]. BPI obtained in such a manner is referred to herein as natural BPI and has been shown to have potent bactericidal activity against a broad spectrum of gram-negative bacteria. The molecular weight of human BPI is approximately 55,000 daltons (55 kD). The amino acid sequence of the entire human BPI protein and the nucleic acid sequence of DNA encoding the protein have been reported in
FIG. 1
of Gray et al.,
J. Biol. Chem.,
264:9505 (1989), incorporated herein by reference.
BPI is a strongly cationic protein. The N-terminal half of BPI accounts for the high net positive charge; the C-terminal half of the molecule has a net charge of −3. [Elsbach and Weiss (1981), supra.] A proteolytic N-terminal fragment of BPI having a molecular weight of about 25 kD has an amphipathic character, containing alternating hydrophobic and hydrophilic regions. This N-terminal fragment of human BPI possesses the anti-bacterial efficacy of the naturally-derived 55 kD human BPI holoprotein. [Ooi et al.,
J. Bio. Chem.,
262: 14891-14894 (1987)]. In contrast to the N-terminal portion. the C-terminal region of the isolated human BPI protein displays only slightly detectable anti-bacterial activity against gram-negative organisms. [Ooi et al.,
J. Exp. Med.,
174:649 (1991).] An N-terminal BPI fragment of approximately 23 kD, referred to as “rBPI
23
,” has been produced by recombinant means and also retains anti-bacterial activity against gram-negative organisms. Gazzano-Santoro et al.,
Infect. Immun.
60:4754-4761 (1992).
The bactericidal effect of BPI has been shown to be highly specific to sensitive gram-negative species, while non-toxic for other microorganisms and for eukaryotic cells. The precise mechanism by which BPI kills gram-negative bacteria is not yet completely elucidated, but it is believed that BPI must first bind to the surface of the bacteria through electrostatic and hydrophobic interactions between the cationic BPI protein and negatively charged sites on LPS. LPS has been referred to as “endotoxin” because of the potent inflammatory response that it stimulates, i.e., the release of mediators by host inflammatory cells which may ultimately result in irreversible endotoxic shock. BPI binds to lipid A, reported to be the most toxic and most biologically active component of LPS.
In susceptible gram-negative bacteria, BPI binding is thought to disrupt LPS structure, leading to activation of bacterial enzymes that degrade phospholipids and peptidoglycans, altering the permeability of the cell's outer membrane, and initiating events that ultimately lead to cell death. [Elsbach and Weiss (1992), supra]. BPI is also capable of neutralizing the endotoxic properties of LPS to which it binds. Because of its gram-negative bactericidal properties and its ability to neutralize LPS, BPI can be utilized for the treatment of mammals suffering from diseases caused by gram-negative bacteria, such as bacteremia or sepsis. Bahrami et al.,
Int'l Endotoxin Soc. Meeting
, Vienna, Austria (August 1992), disclose the use of a BPI protein for the treatment of haemorrhagic shock.
The cells of the reticuloendothelial system (“RES,” also referred to as the “mononuclear phagocytosis system”) include promonocytes and their precursors in the bone marrow, monocytes in the circulation and tissue macrophages including macrophages of the spleen, the liver (Kupffer cells), lungs (alveolar macrophages), connective tissue (histiocytes), bone (osteoclasts), skin (Langerhans cells), central nervous system (microglial cells) and serous cavities (pleural and peritoneal macrophages). Nolan, Gastroenterology; 69: 1346-1356 (1975) and Nolan, Hepatology, 1: 458-465 (1981) review the relationship between endotoxin of gut origin, the reticuloendothelial system and impairment of liver function resulting from e.g., viral infection and hepatic fibrosis as well as exposure to hepatotoxic chemical agents such as carbon tetrachloride. The fixed macrophages, or Kupffer cells, of the liver play a leading role in the RES by clearing and inactivating bacteria and bacterial particulates from the blood stream. In physiological situations, low levels of gut-derived endotoxin are presented to the liver and are detoxified by Kupffer cells of the hepatic RES. Partial hepatectomy results in fewer Kupffer cells and inability to clear and inactivate endogenous endotoxin adequately. Gross et al.
J. Pediatric Surgery
20:320-323 (1985). In addition to these local effects of endotoxin which contribute to hepatic injury, systemic endotoxemia induces catabolic responses including an increased muscle breakdown. This results in increased plasma levels of glutamine which are associated with an increased uptake by the gut and a concomitant greater production of ammonia in the intestinal tract. This increased ammonia load, normally converted to urea in the liver, is insufficiently cleared after partial hepatectomy. It is believed that Kupffer cells are activated and release large amounts of cytokines including TNF and IL-1. See Nathan,
J. Clin. Invest.
79: 319-326 (1987). Moreover, systemic endotoxemia triggers cytokine-release from mononuclear cells in other parts of the body, thus resulting in an amplified catabolic response.
Primary and secondary hepatic neoplasmata represent a significant health problem. Surgical intervention has become a valid therapeutic option but major hepatic resection is still accompanied by a high morbidity and mortality rate. Important postoperative complications include sepsis, hepatic failure and hemorrhage. Massive hepatectomy can also induce renal failure, respiratory failure and impaired myocardial function. Many of these complications closely resemble the effects of sepsis syndrome, van Leeuwen et al.,
Surgery
110: 169-175 (1991) disclose that after liver resection, systemic endotoxemia was provoked which was prevented by preoperative administration of the endotoxin-binding agents cholestyramine or lactulose. See also,
J. of Medicine; Clinical, Experimental
&
Theoretical
, 21(6):301-11(1990) which relates to administration of polymyxin B and attenuation of histological liver injury provoked by endotoxin administration after partial hepatectomy.
Thus, there exists a desire in the art for a treatment that reduces the adverse effects associated with depressed reticuloendothelial system function. In particular, there exists a need for a treatment that reduces the postoperative complications and mortality associated with major hepatic resection.
SUMMARY OF THE INVENTION
The present invention provides novel methods for the treatment of adverse effects associated with depressed reticuloendothelial system function and specifically treatment of adverse physiological effects associated with impaired liver function resulting e.g., from physical, biological and chemical insult to the liver. Conditions associated with impaired RES function include conditions which directly affect the liver including conditions associated with lowered blood flow to the liver via the portal vein or hepatic artery. Such conditions include but are not limited to, liver cirrhosis, liver transplantation, bile duct obstruction and depressed blood flow from t
Boermeester Marja A.
van Leeuwan Paul A. M.
Low Christopher S. F.
Marshall Gerstein & Borun
Mohamed Abdel A.
Xoma Corporation
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