Methods for treating sepsis

Details Methods for treating sepsis Methods for treating sepsis

1999-10-22

2002-02-05

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Enzyme or coenzyme containing

Hydrolases

C514S012200, C514S021800

Reexamination Certificate

active

06344197

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to medical science particularly the treatment of sepsis with protein C in combination with Bactericidal Permeability Increasing (BPI) Protein.
BACKGROUND OF THE INVENTION
Protein C is a serine protease and naturally occurring anticoagulant that plays a role in the regulation of hemostasis by inactivating Factors Va and VIIIa in the coagulation cascade. Human protein C circulates as a 2-chain zymogen, but functions at the endothelial and platelet surface following conversion to activated protein C (aPC) by limited proteolysis with thrombin in complex with the cell surface membrane protein, thrombomodulin.
In conjunction with other proteins, aPC functions as perhaps the most important down-regulator of blood coagulation resulting in protection against thrombosis. In addition to its anti-coagulation functions, aPC has anti-inflammatory effects through its inhibition of cytokine generation (e.g. TNF and IL-1) and also exerts profibrinolytic properties that facilitate clot lysis. Thus, the protein C enzyme system represents a major physiological mechanism of anti-coagulation, anti-inflammation, and fibrinolysis.
Bactericidal permeability-increasing protein (BPI), is a protein isolated from the granules of mammalian polymorphonuclear neutrophils (PMNs). Human BPI has been isolated from PMNs by acid extraction combined with chromatography (Elsbach, 1979,
J. Biol. Chem.
254:11000; Weiss et al. 1987,
Blood
69:652), and has been shown to have potent bactericidal activity against a broad spectrum of Gram-negative bacteria. In addition to its bactericidal effect on Gram negative bacteria, BPI is also capable of binding to and neutralizing lipopolysaccharide (LPS) which is also known as endotoxin because of the inflammatory response that it stimulates.
Sepsis, which includes severe sepsis and septic shock, is a systemic inflammatory response to infection or trauma, associated with and mediated by the activation of a number of host defense mechanisms including the cytokine network, leukocytes, and the complement and coagulation/fibrinolysis systems. [Mesters, et al.,
Blood
88:881-886, 1996]. Disseminated intravascular coagulation [DIC], with widespread deposition of fibrin in the microvasculature of various organs, is an early manifestation of sepsis/septic shock. DIC is an important mediator in the development of the multiple organ failure syndrome and contributes to the poor prognosis of patients with septic shock. [Fourrier, et al.,
Chest
101:816-823, 1992].
Sepsis may be caused by bacterial (either Gram negative or Gram positive), fungal, viral and other infections as well as by non-infective stimuli such as multiple trauma, severe burns, and organ transplantation.
Although sepsis can follow any bacterial infection, it is often associated with a gram negative infection. Sepsis usually begins with tremor, fever, falling blood pressure, rapid breathing and heart beat, and skin lesions. Within hours or days it can progress to spontaneous clotting in the blood vessels, severe hypotension, multiple organ failure, and death.
Most of-the damage comes not from the invading bacteria but from enotoxin. This effect by endotoxin is manifested by its binding to cells such as monocytes/macrophages or endothelial cells, and triggering them to produce various mediators such as tumor necrosis factor-alpha (TNF-&agr;), and various interleukins (IL-1, IL-6, and IL-8). Production of excessive TNF-&agr;) IL-1, IL-6, and IL-8 can elicit septic shock.
There have been numerous recent attempts to treat sepsis in humans, for the most part using agents that block inflammatory mediators associated with the pathophysiology of this disease. However, clinical studies with a variety of agents that block inflammatory mediators have been unsuccessful [reviewed in Natanson, et al.,
Ann. Intern. Med
120:771-783, 1994; Gibaldi,
Pharmacotherapy
13:302-308, 1993]. Since many of the mediators involved in inflammation are compensatory responses, and therefore have salutary effects, some investigators have suggested that blocking their action may not be appropriate [e.g., Parrillo,
N. Engl. J. Med.
328:1471-1477, 1993].
Several encouraging studies using protein C in various animal models of sepsis have been reported. A study in a baboon sepsis model by Taylor, et al., [
J. Clin. Invest.
79:918-25, 1987], used plasma-derived human activated protein C. The animals were treated prophylactically (i.e., the aPC was given at the start of the two hour infusion of the LD
100
E. coli
). Five out of five animals survived 7 days and were considered permanent survivors to the experimental protocol. In control animals receiving an identical infusion of
E. coli
, five out of five animals died in 24 to 32 hours. In addition, plasma-derived human protein C zymogen has been used as a successful adjunct to aggressive conventional therapy in the management of human patients with purpura fulminans in bacterial sepsis (Gerson, et al.,
Pediatrics
91:418-422, 1993; Smith, et al.,
Thromb. Haemost
, PS1709, p419, 1997; Rintala, et al.,
Lancet
347:1767, 1996; Rivard, et al.,
J. Pediatr.
126:646-652, 1995).
Recombinant BPI protein has been shown to neutralize lethal and sublethal effects of endotoxin administered to mice, rats, and rabbits (Fisher, et al., Crit. Care Med., 22(4): 553-558, 1994). Because of this ability to neutralize endotoxin and its Gram-negative bactericidal activity, BPI can be utilized for the treatment of human patients suffering from diseases caused by gram-negative bacteria, including bacteremia, endotoxemia, and sepsis.
The present invention is the first to describe the combination of aPC with BPI in the treatment of sepsis. The combination of aPC and BPI results in a synergy that allows the reduction of the dosages of both aPC and BPI and an improvement of clinical outcome of the patient being treated. The reduction of the dosages of the agents in combination therapy in turn results in reduced side effects that may occur with either agent. Therefore, combining aPC, with its anti-coagulant/anti-inflammatory properties, and BPI, with its bactericidal and endotoxin neutralizing activities will provide an effective synergistic therapy for sepsis that will reduce or ameliorate the adverse events and improve the clinical outcome of septic patients.
SUMMARY OF THE INVENTION
The present invention provides a method of treating a patient suffering from sepsis which comprises administering to said patient a pharmaceutically effective amount of protein C in combination with bactericidal permeability-increasing (BPI) protein.
The present invention further provides a method of treating sepsis in a patient in need thereof, which comprises administering to said patient a pharmaceutically effective amount of BPI protein and activated protein C such that an activated protein C plasma level of about 2 ng/ml to about 300 ng/ml is achieved.
DETAILED DESCRIPTION OF THE INVENTION
For purposes of the present invention, as disclosed and claimed herein, the following terms are as defined below.
Protein C refers to a vitamin K dependent serine protease with anticoagulant, anti-inflammatory, and profibrinolytic properties which includes, but is not limited to, plasma derived and recombinant produced protein C. Protein C includes and is preferably human protein C although protein C may also include other species or derivatives having protein C proteolytic, amidolytic, esterolytic, and biological (anticoagulant, pro-fibrinolytic, and anti-inflammatory) activities. Examples of protein C derivatives are described by Gerlitz, et al., U.S. Pat. No. 5,453,373, and Foster, et al., U.S. Pat. No. 5,516,650, the entire teachings of which are hereby included by reference.
Zymogen—an enzymatically inactive precursor of a proteolytic enzyme. Protein C zymogen, as used herein, refers to secreted, inactive forms, whether one chain or two chains, of protein C.
Activated protein C or aPC refers to protein C zymogen which has been converted by l

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