Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-01-28
2003-09-23
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S013800, C514S014800, C530S300000, C530S324000, C530S325000, C530S326000, C530S344000, C435S252100, C435S252330, C435S253100, C435S253400, C435S254100
Reexamination Certificate
active
06624140
ABSTRACT:
BACKGROUND OF THE INVENTION
Bacterial infections as a complication of surgery, prolonged hospitalization, accidents and other traumatic events, may lead to serious clinical symptoms such as sepsis, septic shock, inadequate organ perfusion, multiple organ failure and acute respiratory distress syndrome (ARDS). Despite advances in medicine over the past decade, an increase in the incidence of sepsis is evident with a mortality rate of 20 to 80%. The sepsis syndrome is initiated when micro-organisms bypass the natural defensive barriers of the body, such as skin and mucous membranes. If the immune system is unable to arrest the infection locally, the organism or its toxins may invade the circulation, where specific bacterial products elicit an inflammatory response that leads to the activation of an array of plasma proteins and cellular defense systems. Although mobilisation of the defence systems of the host is of paramount importance in combatting invading organisms, a cascade of events may simultaneously be triggered that can lead to irreversible tissue injury and organ dysfunction. Uncontrolled infections with Gram-negative bacteria such as
Escherichia coli
, Klebsiella spp., Neisseria spp.,
Pseudomonas aeruginosa
, Salmonella spp, or Bordella spp. or the Gram-positive bacteria
Staphylococcus aureus
, Enterococcus spp., Streptococcus spp.,
Micrococcus luteus
or
Listeria monocytogenes
give rise to a variety of clinical symptoms collectively referred to as the sepsis syndrome. The component of Gram-negative bacteria responsible for the initiation of the host response is termed endotoxin or lipopolysaccharide (LPS), a major glycolipid constituent of the outer membrane. In the circulation, LPS stimulates specific blood cells to produce endogenous mediators of inflammation termed cytokines such as tumor necrosis factor alpha (TNF-&agr;), interleukin-6 (IL-6) and interleukin-8 (IL-8) which have profound physiological effects on the organs and blood vessels of the body. Persistent stimulation of the cellular defence system by excessive LPS leads to overproduction of cytokines which activate a cascade of secondary inflammatory mediators eventually leading to blood vessel damage, circulatory and metabolic disturbances. The toxic component of the LPS molecule is the highly conserved Lipid A moiety which is sufficient to induce the pathophysiological changes characteristic of sepsis.
The prognosis of patients with endotoxemia would be considerably improved if the onset of sepsis could be detected at a sufficiently early stage in the disease process to enable effective treatment. Direct measurement of circulating endotoxins is of importance for the prediction of important clinical events such as bacteremia, septic shock and death. Clinically significant endotoxemia may go undetected by the currently available endotoxin assay, the Limulus amoebocyte lysate assay or LAL test, which has been shown to have serious limitations relating to sensitivity as well as to interference by plasma factors.
Current therapeutic options for Gram-negative bacterial sepsis are limited to anti microbial agents, hemodynamic support and management of sepsis-induced organ dysfunction. Although conventional antibiotic therapy is effective in halting the proliferation of susceptible micro-organisms, the massive release of LPS into the circulation by damaged bacteria may aggravate a septic episode. The relative importance of endotoxin release (endotoxemia) versus bacterial proliferation (bacteremia) during Gram-negative septic shock, however, has not fully been defined. Extensive clinical use of conventional antibiotics such as penicillins, cephalosporins and the like, in the treatment of bacterial infections during the past three decades, has resulted in a dramatic reduction in the efficacy of antibiotic therapy due to an alarming increase in the number of multi-drug-resistant bacteria.
Efforts to intervene directly in the pathophysiological mechanisms which underlie the septic process have yielded inconsistent and largely disappointing results. Anti-endotoxin monoclonal antibodies, anti-cytokine therapies and other anti-inflammatory strategies have proven not to be of sufficient benefit to warrant approval as standard adjunctive therapies for human sepsis. Because of the central role of LPS in the development of the sepsis syndrome, therapies designed to enhance the clearance or to neutralise the detrimental effects of endotoxin may prove beneficial. Therapy targeting the initial interactions of LPS is likely to be of most benefit when administered either early in the pathogenesis before widespread vascular injuries have taken place or prophylactically to high risk patients. However, since it is important to prevent further activation of inflammatory cells during the course of bacterial sepsis there may be a role for such treatment even after septic shock has become established. Characteristics of an anti-endotoxin reagent that would be desirable for therapeutic application include specific and avid binding to LPS concomitant with LPS-neutralizing activity, inherent systemic stability and low cytotoxicity.
A clinical syndrome indistinguishable from Gram-negative septic shock via the same endogenous mediators of inflammation in the absence of endotoxemia may be initiated by Gram-positive bacteria. In this instance, the initiation of the host response has been attributed to lipoteichoic acid (LTA), a major constituent of the outer membrane of Gram-positive bacteria. An additional cell-wall component common to both Gram-negative and Gram-positive bacteria that has been shown to induce cytokines in vitro, is the peptidoglycan and/or naturally occurring breakdown products of this macromolecular structure. Although LPS and LTA share few common structural features, one common physical property of these molecules is amphipathicity, a consequence of a specific orientation of negatively charged hydrophilic groups and hydrophobic side chains of long-chain fatty acid residues. On the basis of recent experimental evidence, a number of common steps in the pathway of cytokine induction by these toxic bacterial cell-wall components has been proposed.
Anti-microbial peptides are generally induced in animals in response to injury and infection. The synthesis of these factors of the innate or non-adaptive immune system may be induced by a variety of stimuli including Grain-positive and Gram-negative bacteria, fungi and viruses. Animal peptide antibiotics are generally small linear or cyclic basically charged molecules such as cecropins and defensins from mammalian and insect cells, magainin from frog skin, melittin from bee venom and tachyplesins from the horseshoe crab hemolymph which act on a rather broad spectrum of microbial organisms that often belong to the natural flora associated with the animal. The antibacterial activity of the linear class of cationic peptide antibiotics has been found to be dependent on the ability to form &agr;-helical structures which are capable of disrupting the integrity of the bacterial outer membrane (OM) by the formation of ion-channels in the lipid bilayer due to self-aggregation of peptide monomers in which the hydrophilic amino acid residues are oriented towards the interior of the membrane pore and the hydrophobic residues at the exterior interacting with phospholipid groups of the cell wall. The molecular basis of the integrity of the OM resides in the electrostatic linkage between the negatively charged Lipid A components of adjacent LPS molecules and divalent cations such as Mg
2+
and Ca
2+
. Disruption of the cross-linkages, by displacement of these cations with positively charged entities of high affinity for LPS, was postulated to result in membrane destabilization. However, previous studies have also indicated that cationicity of an anti-microbial peptide alone is not the sole determinant for OM-permeabilizing activity, but that a specific configuration is essential for high affinity binding to LPS. In addition, since the Lipid A moiety of LPS is not easily accessib
Abraham Philip Richard
Appelmelk Bernard Jan
Van Deventer Sander Jan Hendrik
Academisch Ziekenhuis Bij de Universiteit van Amsterdam Academis
Kam Chih-Min
Low Christopher S. F.
Sughrue & Mion, PLLC
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