Randomized trial of a dry-powder, fibrin sealant in vascular procedures.

Objective: Topical hemostats are important adjuncts for stopping surgical bleeding. The safety and efficacy of Fibrocaps, a dry-powder, fibrin sealant containing human plasma-derived thrombin and fibrinogen, was evaluated in patients undergoing vascular surgical procedures.

Methods: In this single-blind trial (clinicaltrials.

Results from a First-in-Human Trial of a Novel Vascular Sealant.

Background: Suture hole bleeding from synthetic grafts presents a hemostatic challenge. The designs of many vascular sealants are not optimal (non-adherence to wet surfaces, excessive swelling, inflexible). PreveLeak™ (formerly ArterX ((®)) ) is a polyaldehyde-bovine serum albumin-based sealant whose efficacy, safety, and performance were evaluated in this first-in-human study.

Safety and immunogenicity of recombinant human thrombin: a pooled analysis of results from 10 clinical trials.

Study Objective: To evaluate the safety and immunogenicity of recombinant human thrombin (rThrombin), an active topical stand-alone hemostatic agent.

Design: Analysis of pooled data from 10 rThrombin clinical trials.

Patients: A total of 644 adult and pediatric patients treated with rThrombin; 609 patients were included in the immunogenicity analysis.

Immunogenicity and safety of re-exposure to recombinant human thrombin in surgical hemostasis.

Background: This Phase 4, open-label study evaluated the immunogenicity and safety of a second exposure to recombinant human thrombin (rThrombin) in adult patients with previous exposure to rThrombin.

Study Design: Topical rThrombin was applied as a hemostatic aid during a surgical procedure (day 1). Adverse events and clinical laboratory abnormalities were monitored to day 29 (study end).

Persistence of antibodies to the topical hemostat bovine thrombin.

Background: Immunoassays that detect antibovine thrombin product antibodies are not widely available. However, knowing whether these antibodies are present preoperatively would be useful because re-exposure to bovine thrombin-containing products is contraindicated in patients with pre-existing antiproduct antibodies due to the risk of developing immune-mediated coagulopathies. In these exploratory analyses, we characterized one aspect of immune sensitization, the persistence of circulating antibodies after exposure to bovine thrombin product.

Evaluation of recombinant platelet-activating factor acetylhydrolase for reducing the incidence and severity of post-ERCP acute pancreatitis.

Background: Pancreatitis is the most common major complication of diagnostic and therapeutic ERCP. Platelet-activating factor (PAF) has been implicated in the pathophysiologic events associated with acute pancreatitis. Animal and human studies suggested that recombinant PAF acetylhydrolase (rPAF-AH) might ameliorate the severity of acute pancreatitis.

Longitudinal studies of inter-alpha inhibitor proteins in severely septic patients: a potential clinical marker and mediator of severe sepsis.

Objective: To determine the clinical relevance and prognostic significance of serial measurement of inter-alpha inhibitor proteins (IalphaIp) in severely septic patients.

Design: A laboratory-based study of serial plasma samples over the first 5 days of severe sepsis from a prospective clinical trial.

Setting: Small business and academic medical center research laboratories.

Plasma cytokine measurements augment prognostic scores as indicators of outcome in patients with severe sepsis.

Despite recent advances in the prospective identification of the patient with sepsis who may benefit from anti-inflammatory or antithrombotic therapies, successful treatment regimens have been fairly modest. We have explored whether determination of several proinflammatory cytokine or mediator concentrations can complement physiologic scoring systems to identify patients with severe sepsis who will survive or expire within 28 days. The design of the study included an exploratory analysis performed in conjunction with a prospective, randomized, double-blind, placebo-controlled, multicenter, clinical trial and involved 33 academic institutions in the United States.

CD14 receptor occupancy in severe sepsis: results of a phase I clinical trial with a recombinant chimeric CD14 monoclonal antibody (IC14).

Objective: Binding of bacterial cell wall components to CD14 and co-receptors on myeloid cells results in cellular activation and production of proinflammatory mediators. A recombinant anti-CD14 monoclonal antibody (IC14) has been shown to decrease lipopolysaccharide-induced responses in animal and human models of endotoxemia. This study was performed to evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical pharmacology of IC14 in patients with severe sepsis.

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial.

Objective: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction.

An overview of clinical studies in healthy subjects and patients with severe sepsis with IC14, a CD14-specific chimeric monoclonal antibody.

An overview and discussion of clinical studies with IC14, a chimeric monoclonal antibody directed against human CD14 is presented. These studies include phase 1 trials in: (i) healthy subjects; (ii) healthy subjects challenged with lipopolysaccharide (LPS); and (iii) patients with severe sepsis. The results from clinical studies of IC14 demonstrate this chimeric monoclonal antibody diminishes the systemic inflammatory response directed against LPS and may have potential as a treatment to prevent organ dysfunction in patients with severe sepsis.

Effect of IC14, an anti-CD14 antibody, on plasma and cell-associated chemokines during human endotoxemia.

To determine the role of CD14 in lipopolysaccharide (LPS)-induced release of chemokines, 16 humans were injected with LPS (4 ng/kg) preceded (-2 h) by intravenous IC14, an anti-human CD14 monoclonal antibody, or placebo. LPS elicited increases in interleukin (IL)-8 concentrations in plasma and in lysates of red blood cell (RBC), polymorphonuclear cell and mononuclear cell fractions, which were all reduced by IC14. LPS also induced rises in the plasma and RBC levels of monocyte chemoattractant protein (MCP)-1, which were diminished by IC14.

Molecular characterization of the acute inflammatory response to infections with gram-negative versus gram-positive bacteria.

Sepsis caused by gram-negative bacteria and that caused by gram-positive bacteria often manifest similar clinical features. We investigated plasma proinflammatory cytokine profiles in patients with sepsis due to gram-positive and gram-negative bacteria and studied the cytokine production and differential gene regulation of leukocytes stimulated ex vivo with Escherichia coli lipopolysaccharide or heat-killed Staphylococcus aureus. Concentrations of tumor necrosis factor alpha, interleukin 1 receptor antagonist (IL-1Ra), IL-8, IL-10, IL-18 binding protein, procalcitonin, and protein C in plasma did not differ between patients with sepsis due to gram-negative and gram-positive bacteria.

Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb, multicenter, randomized, placebo-controlled, clinical trial.

Objective: Platelet-activating factor (PAF) is a potent proinflammatory mediator implicated in the pathogenesis of both severe sepsis and acute respiratory distress syndrome. One of the regulatory pathways for PAF involves degradation to the inactive metabolite lyso-PAF by the enzyme PAF acetylhydrolase (PAF-AH). Because reduced concentrations of the natural form of PAF-AH have been reported in septic patients, the present study was conducted to determine whether treatment with recombinant human PAF-AH (rPAF-AH, Pafase) was safe when administered after the onset of severe sepsis and whether it decreases the prevalence of acute respiratory distress syndrome and 28-day all-cause mortality.

Treatment with an anti-CD14 monoclonal antibody delays and inhibits lipopolysaccharide-induced gene expression in humans in vivo.

CD14 is a receptor important for activation of cells by lipopolysaccharide (LPS). Treatment with the CD14 antibody IC14 was previously found to attenuate the release of proinflammatory cytokines and some chemokines into the circulation of healthy humans intravenously injected with LPS. To determine the role of circulating leukocytes in CD14-dependent gene expression, 16 healthy volunteers received LPS preceded by either IC14 or placebo.

Effects of IC14, an anti-CD14 antibody, on coagulation and fibrinolysis during low-grade endotoxemia in humans.

To determine the role of CD14 in lipopolysaccharide (LPS)-induced effects on coagulation and fibrinolysis in humans, 16 healthy subjects received an intravenous injection of LPS preceded by intravenous IC14, a recombinant chimeric monoclonal antibody against human CD14, or placebo. LPS-induced coagulation activation (tissue-factor mRNA in whole blood cells and plasma concentrations of F1+2) was not influenced by IC14, whereas the antibody reduced the increase in thrombin-antithrombin complexes and soluble fibrin. LPS injection also was associated with an early activation of fibrinolysis (plasma concentrations of tissue-type plasminogen activator and plasmin-alpha(2)-antiplasmin complexes), followed by an inhibitory response (plasminogen activator inhibitor type 1), which were attenuated by IC14.