Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-07-14
2001-10-23
Smith, Lynette R. F. (Department: 1645)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S005000, C435S007100, C435S007240, C435S007310, C435S007320, C435S024000, C435S034000, C435S962000, C435S968000, C435S975000, C436S513000, C436S518000, C436S536000, C436S808000, C436S811000
Reexamination Certificate
active
06306614
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to methods to measurement of the level of an analyte in a sample of blood. Analytes may include infectious miicroorganisms, their toxic products, inflammatory mcdiators, hormones, acute phase proteins, toxins, drugs of abuse, nlarkecrs of cardiac muscle damagye, therapeutic drugs, cytokines, chemokines, and others.
DEFINITIONS
“Analyte” is defined as the specific substance of interest present in a bodily fluid sample and being analyzed by tlhe methods of thei present invention. In the case of analytes related to infection and sepsis, these may include, for example, microorganisms and their components, including gram positive cell wall constituents and gram negative endotoxin, lipopolysaccharide. lipoteichoic acid, and the inflammatory mediators that appear in circulation as a result of the presence of these components, including tumor necrosis factor (TNF), interleukin-1 (IL-1) and other interleukins and cytokines. Other analytes may include drugs of abuse, hormones, toxins. therapeutic drugs, markers of cardiac muscle damage, etc.
“Sepsis” is defined as a pathological condition of the body resulting from the presence of infectious microorganisms, which clinically manifests as one or more of the following sequelae: pyrexia, hypotension, hypoxcmia, tachycardia, hypothermia, neutroplhilia, and neutropenia.
“Immunocomplexes” is a synonym for antibody-antigen complexes.
“Opsonized” refers to a particle to which immunoglobulin and complement factors are bound and which results in a more vigorous recognition of the particle by the immune system. For example. the yeast polysaccharide zymosan, or latex particles, may be opsonized by binding of immunoglobuliln and complement factors to their surfaces; opsonized zymosan or latex will stimulate increased oxidant production by white cells after they are activated by exposure to immunocomplexes.
“Responsiveness” is a measure of the patient's ability to respond to a maximum stimulatory dose of immunocomplex.
BACKGROUND OF THE INVENTION
Rapid quantitation of'specific analytes in an individual's blood is critically important for the diagnosis of disease and its severity, often under emergency conditions. in the monitoring of the progression of pathological conditions and following the recovery process brought about by surgical and drug therapies. It is often important to know not only whether a specific analyte is presents but as well its level, in order to determine the present stage of a particular condition or disease in order to prescribe the most effective remedy at that particular stage. In the treatment of many diseases, a particular therapy may be ineffective or toxic if given at the wrong stage of the condition. For example, the levels of specific markers of cardiac muscle damage and the relationship among them may indicate that a patient has had or may be having a heart attack. The level of a therapeutic drug in the circulation may indicate whether the patient is being dosed optimally, and whether presumptive side effects are possibly due to excess levels of the drug. In infection and sepsis, the circulating levels of infectious microorganism-derived toxins and inflammatory mediators produced by the patient's white blood cells in response to these toxins may indicate the severity and level or stage of sepsis and help identify the most efficacious course of therapy. Quantitation of analytes under emergency conditions and using the information to prescribe a particular therapy may mean the difference between saving a patient's life and contributing to the patient's death. For example, in the case of infection, hospital and particularly intensive care unit patients who have acquired nosocomial infections as a result of peri- or post-operative immunosuppression or infections secondary to other disease proccsscs, such as pancreatitis, hypotensive or hypovolemic shock, physical trauma, burn injury, or organ transplantation, and subsequently develop septic shock syndrome, have a mortality which has been quoted to range from 30-70% dcpending upon other co-incident complications. Despite the development of increasingly potent antimicrobial agents, the incidence of nosocomial infections and, in particular, infections leading to sepsis or septicemia, is increasing. The difficulty with many ol the promising therapeutic agients is that their window of opportunity and indications for use have not been adequately delineated largely due to a lack ot appropriate rapid and quantitative diagnostic procedures and partly due to a lack ol complete understanding of the pathogenesis of the sepsis syndrome.
The presence of bacteria, viruses or fungi or their cell wall components including gram-positive peptidoolycans, lipoteichoic and teichoic acids, and gram-negative endotoxin (lipopolysaccharide, LPS) in blood is indicative of an infection. In addition, the immune system's reaction to the presence of these foreign antioens by the production of pro-inflammatory cytokine mediators such as interleukin-1 (IL-1), tumor necrosis factor (TNF) and interleukin-6 (IL-6), is also indicative ol an infection. The quantity of these analytes in circulation may be used to indicate the severity and level or stage of sepsis. For instance, at an early stage of Gram-negative sepsis, LPS may be present at a concentration as low as 50 pg/ml of whole blood. At the next stage, sepsis has progressed and a mediator of sepsis, TNF, can be detected and measured using antibody against TNF. At stage 3. TNF may be present in smaller amounts since it is transitory and another transitory mediator, IL-1, may appear. As sepsis progresses further, LPS levels may decrease and TNF be absent, but IL-1 may increase and interleukin-6 (IL-6) may appear. Finally, in a more prolonged case of sepsis, LPS may be present and IL-1 may be at low levels but IL-6 may be at very high levels. Tlhus, diagnosis of sepsis and identifying its stage in the course the disease are critical for the successful treatment of this serious and potentially lethal consequence of infection. Quantitation of the levels of the sepsis-associated analytes provide information necessary to determine the best course of therapy to treat the acute disease.
Currently, one of the major problems with many of the therapeutic protocols being tested by the pharmaceutical companies conducting clinical trials in sepsis intervention is their inability to rapidly detect early and evolving sepsis. The results of blood cultures may arrive too late. Otlher septicaemia tests are also time consuming and may not be sensitive enough for early detection. Centocor Inc.'s immunometric assay for tumor necrosis factor-alpha (TNF-&agr;). as described in WO 90/06314. uses two antibodies, one of which is labeled. The National Aeronautics and Space Administration detects P,seu(titmonloas bacteria by extraction of Azurin and detection using Azurin-specific antibody (U.S. Pat. No. 7,501,908). The endotoxin assay kit from Bio Whittaker (Walkerville, Md., U.S.A.) or Seikagaku Kogyo Ltd. (Tokyo Japan) is a Limulus Amebocyte Lysate (LAL) Assay technique which may be used as a comparison for the present invention.
Many investigators versed in the complexities of the septic response believe that treatment is ineffectual for patients who already manifest the classical clinical symptoms of sepsis (i.e., hyperdynamic circulation hypotension, decreased systemic vascular resistance, pyrexia and increased oxygen dependency). Thee course of the inflammatory process has progressed too far for many of the interventions to benefit the patient since the multiple interacting inflammatory cascades with which the body attempts to eliminate the infectious challenge are in many instances at their nadir and difficult to control pharmacologically. Thus, a major clinical and diagnostic challenge is to identify and stage patients, ideally early in the progression of the septic response, or to identity those patients at high risk of developing fulminant sepsis syndrome. The same therapeutic
Romaschin Alexander D.
Walker Paul M.
Baskar Padma
Klauber & Jackson
Sepsis, Inc.
Smith Lynette R. F.
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