Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
2000-02-01
2002-06-18
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
C514S002600, C514S008100, C514S012200
Reexamination Certificate
active
06406688
ABSTRACT:
FIELD OF INVENTION
This invention relates to the method of preventing and treating sepsis and adult respiratory distress syndrome using certain chemokines or biologically active fragments thereof alone or in conjunction with an anti-infective agent or hematopoietic maturing agent.
BACKGROUND OF INVENTION
Sepsis, as used herein, is broadly defined to mean situations when the invasion of a host by a microbial agent is associated with the clinical manifestations of infection including but not limited to:
(1) temperature >38° C. or <36° C.; (2) heart rate >90 beats per minute; (3) respiratory rate >20 breaths per minute or PaCO
2
<32 mm Hg; (4) white blood cell count >12,000/cu mm, <4,000/cu mm, or >10% immature (band) forms; (5) organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to lactic acidosis, oliguria, or an acute alteration in mental states. (Chest 1992; 101: 1644-1566).
Sepsis can occur in hospitalized patients having underlying diseases or conditions that render them susceptible to bloodstream invasion or in burn, trama or surgical patents. In many cases of sepsis, the predominant pathogen is
Escherichia coli
, followed by other Gram-negative bacteria such as the Klebsiella-Enterobacter-Serratia group and then Pseudomonas. Although comprising a somewhat smaller percentage of infection, Gram-positive microbes such as Staphylococcus and systemic viral and fungal infections are included by the term sepsis as used herein. The genitourinary tract is the most common site of infection, the gastrointestinal tract and respiratory tract being the next most frequent sources of sepsis. Other common foci are wound, burn, and pelvic infections and infected intravenous catheters.
A serious consequence of bacterial sepsis often is septic shock. Septic shock is characterized by inadequate tissue perfusion, leading to insufficient oxygen supply to tissues, hypotension and olgiuria.
Septic shock occurs because bacterial products react with cells and components of the coagulation, complement, fibrinolytic and bradykinin systems to release proteases which injure cells and alter blood flow, especially in the capillaries.
Microorganisms frequently activate the classical complement pathway, and endotoxin activates the alternative pathway. Complement activation, leukotriene generation and the direct effects of bacterial products on neutrophils lead to accumulation of these inflammatory cells in the lungs, release of their proteolytic enzymes and toxic oxygen radicals which damage the pulmonary endothelium and initiate the adult respiratory distress syndrome (“ARDS”). ARDS is a major cause of death in patients with septic shock and is characterized by pulmonary congestion, granulocyte aggregation, haemorrhage and capillary thrombi.
Septic shock is a major cause of death in intensive care units. There are an estimated 200,000 cases per year of septic shock in the United States, and despite advances in technology (i.e., respiratory support) and antibiotic therapy, the mortality rate for septic shock remains in excess of 40%. In fact, mortality for established septic shock has decreased very little since the comprehensive description by Waisbren (
Arch. Intern. Med
. 88:467-488 (1951)). Although effective antibiotics are available, and there is an increased awareness of the septic shock syndrome, the incidence of septic shock over the last several decades has actually increased. With the appreciation that antimicrobial agents have failed to completely abrogate septic mortality, it is clear that other agents must be developed to be used alone or in conjunction with antimicrobials in order to rectify the deficiencies of current established therapy.
BRIEF DESCRIPTION OF THE INVENTION
This invention relates to a method of preventing or treating sepsis and ARDS comprising administering to an animal, including humans, in need thereof an effective amount of chemokine protein or biologically active fragments thereof.
This invention further relates to a method of preventing or treating sepsis and ARDS comprising administering to an animal (including humans) in need thereof an effective amount of chemokine protein or biologically active fragments thereof, either before, in conjunction with or after an anti-infective agent.
DETAILED DESCRIPTION OF THE INVENTION
It is the object of this invention to provide a new method of treatment of sepsis and ARDS comprising administering to an animal in need thereof, including humans, an effective amount of chemokine protein or biologically active fragments thereof, alone or in combination with other anti-infective agents. As used herein the term “chemokine” means Chemokine Beta-4 (SEQ ID NOs: 1 and 2). The initial 24 amino acids represent the deduced leader sequence of Chemokine Beta-4 such that the putative mature polypeptide comprises 72 amino acids.
TABLE 1
Chemokine Patent Applications
Application
Gene Name
Date Filed
Number
Macrophage Inflammatory
Dec-22-93
08/173,209
Protein-Gamma
Macrophage Inflammatory Protein-3
Mar-8-84
WO95/17092
and -4
Macrophage Migration Inhibitory
May-16-94
WO95/31468
Factor-3
Human Chemokine Beta-9
Jun-6-95
WO96/06169
Human Chemokine Polypeptides
Aug-23-94
WO96/05856
Human Chemokine Beta-11 and Human
Feb-8-95
US95/01780
Chemokine Alpha 1
Human Chemokine Beta-13
Jun-5-95
08/464,594
Human Chemokine Beta-12
Jun-6-95
08/468,541
Chemokine Alpha-2
Mar-19-96
60/013,653
Chemokine Alpha-3
Mar-18-96
US96/03686
Novel Chemokine for Mobilizing
Sep-29-95
60/006,051
Stem Cells
Short Form Chemokine Beta-8
Oct-24-95
60/004,517
This invention further relates to a method of preventing sepsis and ARDS comprising administering to an animal in need thereof an effective amount of modified chemokine protein or biologically active fragments thereof alone or in combination with other anti-infective agents.
Known anti-infective agents include, without limitation, anti-microbial agents routinely used for the treatment of sepsis such as amino-glycosides (such as amikacin, tobramycin, netilmicin, and gentamicin), cephalosporins such as ceftazidime, related beta-lactam agents such as maxalactam, carbopenems such as imipenem, monobactam agents such as aztreonam; ampicillin and broad-spectrum penicillins, (e.g., penicillinase-resistant penicillins, ureidopenicillins or antipseudomonal penicillin or Augmentin) that are active against
P. aeruginosa
, Enterobacter species, indole-positive Proteus species, and Serratia. Also included within the definition of anti-infective agents are antifungal agents, amphotericin and the like as well as anti-viral agents such as famvir and acyclovir.
The compound is useful in the treatment and prevention of sepsis and ARDS in humans and other animals such as dairy cattle, horses, calves or poultry.
Chemokine protein or biologically active fragments of Chemokine Beta-4 have been described. The use of chemokine protein or biologically active fragments thereof for the prevention and treatment of sepsis has not been reported. It has now been discovered that chemokine protein or biologically active fragments thereof significantly increases the survival of animals challenged with lethal sepsis causing organisms. Treatment with the compound of this invention, alone or in combination with an anti-infective agent prior to contemplated thoracic or abdominal surgery would be useful in reducing the likelihood of post-operative sepsis. It may also be used post-operatively for the treatment of sepsis and ARDS caused by a variety of reasons as outlined previously.
To effectively treat a human or other animal chemokine protein or biologically active fragments thereof may be amstered by injection in the dose range of about 10 fg/kg to about 100 mg/kg/dose, preferably between about 1 and 50 mg/kg/dose, or orally in the dose range of about 10 fg/kg to about 100 mg/kg body weight per dose, preferably between about 1 and 50 mg/kg body weight; if administered by infusion or similar techniques, the dose may be in the range of about 10 fg/kgto about
Pelus Louis Martin
White John Richard
Human Genome Sciences Inc.
Mertz Prema
Sterne Kessler Goldstein & Fox P.L.L.C.
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