Chemistry: molecular biology and microbiology – Maintaining blood or sperm in a physiologically active state...
Reexamination Certificate
2002-07-18
2004-10-12
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Maintaining blood or sperm in a physiologically active state...
C210S501000, C210S633000
Reexamination Certificate
active
06803183
ABSTRACT:
BACKGROUND OF THE INVENTION
General Background and State of the Art
This invention is directed to methods for pyrogen removal from plasma and whole blood.
The presence of pyrogens in the blood is responsible for inflammatory reactions that, if they go unchecked, can be fatal, such as in the case of septic shock. Currently, the leading cause of death in intensive care units (ICUs) is multiple organ failure (MOF). The mortality of patients in ICUs due to septic shock is about 30%. There are approximately 500,000 patients per year suffering from sepsis in the U.S., and the number of deaths related to sepsis syndrome is increasing every year (200,000 deaths/year) as well as the death rate. Decades of research to overcome septicemia or even decrease the mortality rate have been unsuccessful and disheartening.
The concept of MOF was developed in 1975. In the etiology of MOF, the frequency of infection, sepsis, and inflammation is very high. The original classification of Bone (Bone, Crit Care Med 1989, 7:389-393), identifying sepsis and septic shock was later revised (Members of the American College of Chest Physicians 1992), and a new terminology was developed. The definition of systemic inflammatory response syndrome and the multiple organ dysfunction syndrome (MODS) were worked out. Sepsis, severe sepsis and septic shock were also redefined. The Marshall score (Marshall, Crit Care Med 1995, 23:1638-1652) has been accepted to describe the severity of MODS.
The pathogenesis of sepsis begins with the proliferation of microorganisms at a nidus of infection followed by invasion of the bloodstream and other organs. Gram-negative bacteria account for a large fraction of cases of sepsis. The structural component of Gram-negative bacteria, endotoxin (ET) or lipopolysaccharide (LPS), plays a pivotal role in the initiation and development of the sepsis syndrome. The most widely accepted theory of sepsis is based on the following line of thought. ET binds to the CD14 receptor and leads to the activation of monocytes and other cells carrying this receptor. The binding results in transcriptional changes in the nucleus of activated cells, and the synthesis of different inflammatory compounds, such as Platelet Activating Factor-1, pro-inflammatory cytokines such as TNF-&agr;, Interleukin-1 (IL-1) or IL-6 leading to a systemic inflammatory response.
The immunological pattern of sepsis has a biphasic manifestation. The early hyper-inflammatory phase is counterbalanced by an anti-inflammatory response (the release of soluble cytokines and cytokines receptors, e.g. IL-10, IL-1 Receptor antagonist and the synthesis of anti-cytokine antibodies). The induction of imbalanced production of different cytokines is part of the pathology of septic shock. When the anti-inflammatory response is in measure with the hyper-inflammatory reactions, the clinical outcome is usually favorable. However, either the hyper-inflammatory or the anti-inflammatory mechanism may become uncontrolled, leading to serious organ damage, organ failure and death. In this frame of thinking, early mortality is related to excessive systemic inflammatory response, while late mortality is caused by immunodepression, in the late, so-called hypo-inflammatory state, also called the state of terminal immuno-paralysis (Kox, Int Care Med 2000, 26:S124-128).
In the vast majority of septic shock cases, disseminated intravascular coagulation (DIC) is also diagnosed, and that DIC often leads to different organ failures. The relationship between ET and DIC has been investigated. In animal models, ET is often used to induce DIC. It has been thought that in those cases, DIC is primarily initiated by injury to the capillary endothelium, and that changes on the endothelial surface contribute to the development of DIC (Miyashima, Acta Med Okayama 1989, 43(2): 115-126).
Gram-negative septicemia elicits multiple abnormalities of the coagulation system. Although products of coagulation can lead to clot formation, potentiating organ damage, it has also been shown that low concentrations of thrombin can protect animals from the shock state by leading to in vivo formation of activated Protein C, an anticoagulant enzyme. In baboons, when
E. coli
was used to induce sepsis, lethal responses were prevented by infusion of exogenous Protein C (Taylor, J Clin Inves 1987, 79:918-925).
Because of the complexity of the pathology and the numerous factors involved, the treatment of sepsis has proved itself to be difficult, expensive and so far an unrewarding task.
With the emergence of antibiotic-resistant infections, the treatment of sepsis has become even more difficult. A number of microorganisms are of great concern in terms of their resistance. For example, Methicillin-Resistant
Staphylococcus aureus
has become an important cause of infection, not only in the ICUs of hospitals, but in the community as well. Strains of Vancomycin-Intermediate
S. aureus
have also recently been identified (Sieradzki, N Engl J Med 1999, 340:517-523; Smith, N Engl J Med 1999, 340:493-501). They are difficult to detect with standard laboratory methods, which increases the risk they represent. Vancomycin-Resistant Enterococci infections have increased 47% among ICU patients in the last five years.
The great majority of therapeutic modalities for sepsis of the last decade, include treatments with antibodies, soluble receptors and recombinant protein constructs to block the effect of one or another mediator contributing to the circulatory collapse, MOF and death of sepsis patients. They were based on the concept of sepsis characterized by changes in pro-inflammatory mediators, cytokines, growth factors and lipid metabolites. Synergen initiated three trials with Antril (IL-1 receptor antagonist). The drug had no significant effect in septic patients (Opal, Crit Care Med 1997, 25(7): 1115-1124; Fisher, Crit Care Med 1994, 22(1):12-21 and JAMA 1994, 271(23):1836-1843). Platelet activating factor antagonist (Dhainaut, Crit Care Med 1994, 22(11): 1720-1728 and 1995, 23(9):1461-1469), bradykinin antagonists [Rodell, Press release Cortech Inc, Jul. 18, 1995; Fein, JAMA 1997, 277(6):482-487), anti-TNF antibodies [Reinhart, Crit Care Med 1996, 24:733-792; Fisher, Grit Care Med 1993, 21(3):318-327; Dhainaut, Crit Care Med 1995, 23(9):1461-1469; Abraham, JAMA 1995, 273(12):934-941; Cohen, Crit Care Med 1996, 24 (9):1431-1440), soluble TNF receptors (Fisher, N Engl J Med 1996, 334(26):1697-1702; Abraham, JAMA 1995, 273(12):934-941) and prostaglandin antagonists (Bernard, N Engl J Med 1997,336(13):912-918; Haupt, Crit Care Med 1991, 19(11):1339-1347; Bernard, Am Rev Respir Dis 1991,144(5):1095-1101) were also tried in recent clinical investigations. None of these clinical trials succeeded in identifying an effective new treatment modality for septic shock.
There are current trials still in process. Most recently, results of a phase 3 clinical trial were reported (Bernard, N Engl J Med 2001, 344(10): 699-709). Dotrecogin &agr;-activated (24 &mgr;g/kg i.v.) was used in that multi-center trial, and a 6.1% reduction in the absolute risk of death was achieved.
For now, the standard treatments of septic shock continue to be urgent stabilization of the patient, volume resuscitation, vasopressors and/or inotropic therapy to restore perfusion, and the administration of broad spectrum, empirical antibiotic therapy in the setting of an ICU. Monitoring strategies and adjunctive therapy are also useful.
High ET levels are consistently measured in the blood of patients with severe septic shock syndrome. In many cases, the clinical picture correlates with the level of LPS in the blood of the patients. Removal of ET from their blood remains to be ultimately desirable. The LPS theory has been extensively explored, and results show that once the cascade of LPS, CD14, pro-inflammatory proteins and cytokines has been set in motion, further active downstream substances are produced, and they contribute to the often irreversible pathophysiology of the disease. With regard to the administration of LPS antibodie
Amoureux Marie-Claude
Grandics Peter
Hegyi Edit
Szathmary Susan
Catalyst Law Group APC
Clarigen, Inc.
Farber, Esq. Michael B.
Saucier Sandra E.
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