Method of treating sepsis and ARDS using chamohine beta-10

Details Method of treating sepsis and ARDS using chamohine beta-10 Method of treating sepsis and ARDS using chamohine beta-10

1997-05-06

2001-09-18

Mertz, Prema (Department: 1646)

Drug, bio-affecting and body treating compositions

Lymphokine

C514S002600, C514S008100, C514S012200, C514S885000, C514S921000

Reexamination Certificate

active

06290948

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 those polypeptides claimed in the patent applications set forth in Table 1.
TABLE 1
Chemokine Patent Applications
Application
Gene Name
Date Filed
Number
Macrophage Inflammatory Protein-
22-Dec-93
08/173,209
Gamma
Macrophage Inflammatory Protein-3
8-Mar-84
WO95/17092
and -4
Macrophage Migration Inhibitory
16-May-94
WO95/31468
Factor-3
Human Chemokine Beta-9
6-Jun-95
WO96/06169
Human Chemokine Polypeptides
23-Aug-94
WO96/05856
Human Chemokine Beta-11 and Human
8-Feb-95
US95/01780
Chemokine Alpha-1
Human Chemokine Beta-13
5-Jun-95
08/464,594
Human Chemokine Beta-12
6-Jun-95
08/468,541
Chemokine Alpha-2
19-Mar-96
60/013,653
Chemokine Alpha-3
18-Mar-96
US96/03686
Novel Chemokine for Mobilizing Stem
29-Sep-95
60/006,051
Cells
Short Form Chemokine Beta-8
24-Oct-95
60/004,517
Table 2 displays the CDNA sequence (SEQ ID NO:1) and corresponding deduced amino acid sequence of chemokine beta-10 (Ck&bgr;-10) (SEQ ID NO:2). The initial 23 amino acids represent the putative leader sequence of Ck&bgr;-10 such that the putative mature polypeptide comprises 75 amino acids. The standard one-letter abbreviation for amino acids is used.
TABLE 2
ATGAAAGTTTCTGCAGTGCTTCTGTGCCTGCTGCTCATGACAGCAGCTTTCAACCCCCAG
M  K  V  S  A  V  L  L  C  L  L  L  M  T  A  A  F  N  P  Q
GGACTTGCTCAGCCAGATGCACTCAACGTCCCATCTACTTGCTGCTTCACATTTAGCAGT
G  L  A  Q  P  D  A  L  N  V  P  S  T  C  C  F  T  F  S  S
AAGAAGATCTC(TTGCAGAGGCTGAAGAGCTATGTGATCACCACCAGCAGGTGTCCCCAG
K  K  I  S  L  Q  R  L  K  S  Y  V  I  T  T  S  R  C  P  Q
AAGGCTGTCATCTTCAGAACCAAACTGGGCAAGGAGATCTGTGCTGACCCAAAGGAGAAG
K  A  V  I  F  R  T  K  L  G  K  E  I  C  A  D  P  K  E  K
TGGGTCCAGAATTATATGAAACACCTGGGCCGGAAAGCTCACACCCTGAAGACTTGA
W  V  Q  N  Y  M  K  H  L  G  R  K  A  H  T  L  K  T  *
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

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