Treatment of Septic Shock with Human Monoclonal Antibody HA-1A

McCloskey, Richard V.

doi:10.7326/0003-4819-121-1-199407010-00001

Cited by 445 publications

(56 citation statements)

References 8 publications

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“…Furthermore, therapies directed against endotoxin (10), TNF-␣ (8), and IL-1 ␤ (9) improve survival in animal models. These preclinical results, however, have not translated into significant beneficial outcomes in human clinical trials of anticytokine and antiendotoxin therapies in sepsis (1,(3)(4)(5)(6)(7). It is unknown if this failure relates to the bioactivity of the agents studied, the methodologies used, or the hypotheses tested (1,16,17).…”

Section: Introductionmentioning

confidence: 99%

“…Most previous attempts at blocking inflammation during sepsis have been limited to targeting a single mediator in one compartment of the body (i.e., the circulation) (1,(3)(4)(5)(6)(7)(8)(9)(10). In contrast, tyrosine kinase inhibitors act directly on cells, not mediators.…”

Section: Introductionmentioning

confidence: 99%

“…(1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). In this view of septic shock pathogenesis, endotoxin and other bacterial products initiate an inflammatory response by activating sentinel cells that release cytokines, including TNF-␣ and IL-1 ␤ (1, [8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.

Sevransky¹,

Shaked²,

Novogrodsky³

et al. 1997

J. Clin. Invest.

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Tyrosine kinase-dependent cell signaling is postulated to be a pivotal control point in inflammatory responses initiated by bacterial products and TNF. Using a canine model of gram-negative septic shock, we investigated the effect of tyrosine kinase inhibitors (tyrphostins) on survival. Animals were infected intraperitoneally with Escherichia coli 0111: B4, and then, in a randomized, blinded fashion, were treated immediately with one of two tyrphostins, AG 556 ( n ϭ 40) or AG 126 ( n ϭ 10), or with control ( n ϭ 50), and followed for 28 d or until death. All animals received supplemental oxygen, fluids, and antibiotics. Tyrphostin AG 556 improved survival times when compared to controls ( P ϭ 0.05). During the first 48 h after infection, AG 556 also improved mean arterial pressure, left ventricular ejection fraction, cardiac output, oxygen delivery, and alveolar-arterial oxygen gradient compared to controls (all P Յ 0.05). These improvements in organ injury were significantly predictive of survival. Treatment with AG 556 had no effect on clearance of endotoxin or bacteria from the blood (both P ϭ NS); however, AG 556 did significantly lower serum TNF levels ( P ϭ 0.03). These data are consistent with the conclusion that AG 556 prevented cytokine-induced multiorgan failure and death during septic shock by inhibiting cell-signaling pathways without impairing host defenses as determined by clearance of bacteria and endotoxin. ( J. Clin. Invest. 1997. 1966-1973.) Key words: tyrosine kinase inhibitor • cell signaling pathways • septic shock • multiorgan failure

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.

Sevransky¹,

Shaked²,

Novogrodsky³

et al. 1997

J. Clin. Invest.

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“…Clinical trials have been carried out with the anti-cycloxygenase drug ibuprofen to reduce levels of arachidonate metabolites [68], with the anti-oxidants N-acetylcysteine (NAC) and L -2-oxothiazolidine-4-carboxylate to reduce oxidative stress in septic patients [69], with TNF-α receptor-blocking recombinant reagents of with anti-TNF-α antibodies [70, 71], with recombinant human IL-1 receptor antagonist [72] or with anti-endotoxin antibodies [73] with discouraging results. Anti-coagulant factors have been used to prevent or treat micro-intravascular coagulation [74], and protein C activated has met expectations, being not only effective but also cost effective [75].…”

Section: Clinical Applicationsmentioning

confidence: 99%

Immunogenetics of Severe Respiratory Infections: Models for the Development of New Therapeutic Strategies

Bocchino

Marruchella²,

Saltini³

2005

Respiration

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Innate and adaptive immunity plays a critical role in the defence of the lung and other mucosal surfaces exposed to micro-organisms. Anti-microbial peptides and proteins, cytokines and chemokines are important immune weapons as they build up the protective front for the respiratory tract. The notion that susceptibility to infectious diseases may be inherited is widely accepted and, as it is the failure to activate adaptive immunity that may allow infection to become established and progress toward invasion and dissemination, the recognition of specific gene defects affecting the ability of the immune system to overcome invading pathogens may shed light upon those mechanisms of immune regulation that are playing the most critical roles. The aim of the present review is to discuss some of the advances in infection immunogenetics that may lead to identify new strategies in the development of new anti-infectious and anti-inflammatory drugs.

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“…Efforts to interfere directly in the pathophysiologic mechanisms which underlie the septic process have yielded inconsistent and largely disappointing results. Antiendotoxin monoclonal antibodies (11,18), anticytokine therapies (1,6,8), and other anti-inflammatory strategies (5,24) have not proven to be of sufficient benefit to warrant approval as standard adjunctive therapies for human sepsis.…”

mentioning

confidence: 99%

Activity of lipopolysaccharide-binding protein-bactericidal/permeability-increasing protein fusion peptide in an experimental model of Pseudomonas sepsis

Opal

Palardy

Jhung

et al. 1995

Antimicrob Agents Chemother

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A chimeric protein consisting of the N-terminal domain of lipopolysaccharide-binding protein and the C-terminal domain of bactericidal/permeability-increasing protein demonstrated a dose-dependent survival benefit (P ‫؍‬ 0.001) and reduced endotoxin levels (P < 0.01) in neutropenic rats with Pseudomonas aeruginosa sepsis. This lipopolysaccharide-binding protein-bactericidal/permeability-increasing peptide has favorable pharmacokinetics and antiendotoxin properties which may be of value for human sepsis.Current therapeutic options for gram-negative bacterial sepsis are limited to antimicrobial agents, hemodynamic support, and management of sepsis-induced organ dysfunction (4). Efforts to interfere directly in the pathophysiologic mechanisms which underlie the septic process have yielded inconsistent and largely disappointing results. Antiendotoxin monoclonal antibodies (11, 18), anticytokine therapies (1,6,8), and other anti-inflammatory strategies (5, 24) have not proven to be of sufficient benefit to warrant approval as standard adjunctive therapies for human sepsis.Despite these setbacks, it is anticipated that refinements in clinical trial design and innovations in the synthesis of more potent therapeutic agents will lead to significant advances in the treatment of sepsis in the future. A naturally occurring endotoxin-binding and neutralizing protein which may prove to be particularly effective in endotoxemic states is bactericidal/ permeability-increasing protein (BPI) (17,25). This cationic human neutrophil-derived, 456-amino-acid protein is known to possess potent endotoxin neutralizing properties and intrinsic antimicrobial actions (16,20,26). It has recently been shown that BPI is protective in a variety of endotoxin challenge experiments both in vitro (3, 9, 19) and in vivo (2, 7, 16).A potential limitation to the therapeutic utility of BPI in clinical endotoxic shock is its rapid clearance from the central circulation, with a plasma half-life of only 2 to 4 min in experimental animals (7). A recombinant fusion construct of human BPI with a closely related endotoxin-binding protein, known as lipopolysaccharide (LPS)-binding protein (LBP) (23, 27), has been generated; this combines the endotoxin-neutralizing properties of BPI with the favorable clearance properties of LBP. BPI and LBP are genetically (10) and structurally (26) related proteins, yet they have opposing physiologic actions in the presence of LPS (12,22). BPI inhibits interactions between LPS and CD14-bearing effector cells such as neutrophils and monocytes. LBP, in contrast, facilitates the delivery of LPS to CD14 antigens on cell membranes and potentiates LPS activity.A chimeric protein consisting of the first 199 amino acids of the amino terminus of LBP and the C-terminal 257 amino acids of BPI was found to possess desirable attributes of both LBP and BPI in endotoxin challenge models (15). This fusion peptide was tested in a bacteremic infection model of Pseudomonas aeruginosa sepsis in neutropenic rats.(This paper was presented in part ...

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Treatment of Septic Shock with Human Monoclonal Antibody HA-1A

Cited by 445 publications

References 8 publications

Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.

Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.

Immunogenetics of Severe Respiratory Infections: Models for the Development of New Therapeutic Strategies

Activity of lipopolysaccharide-binding protein-bactericidal/permeability-increasing protein fusion peptide in an experimental model of Pseudomonas sepsis

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