ALBERT

Description: Background: The Duffy receptor is a promiscuous receptor for chemokines that binds selected members of both the C-X-C and C-C families with high affinity. Duffy antigen may influence plasma levels of proinflammatory cytokines by acting as a “chemokine sink”. Additionally, Duffy knockout mice experienced an exaggerated response to endotoxin in comparison to wild-type mice. The current trial was designed to elucidate the functional role of the Duffy blood group antigen in human inflammation. We hypothesized that “Duffy negative“ volunteers might show an increased inflammatory response to endotoxin (LPS) infusion in terms of cytokine response. The human endotoxemia model is a well established model of systemic inflammation, where a well defined, self-limited inflammatory stimulus permits the elucidation of key players involved in the inflammatory response. We therefore used this model to investigate the functional role of the Duffy Antigen Receptor Complex (DARC) in the inflammatory response after endotoxin challenge. Methods: Thirty-two healthy male volunteers received an intravenous infusion of 2ng/kg endotoxin, 16 Caucasians (Duffy antigen positive on erythrocytes) and 16 subjects of African descent (“Duffy negatives”). Cytokines, chemokines, as well as their receptors were quantified by ELISA, RT-PCR and FACS. Results: Plasma levels of TNF, IL-6, IL-8 and IL-8 mRNA in whole blood increased to a similar extent in both groups after LPS infusion. In contrast, peak MCP-1 levels at 3 hours were roughly 2-fold higher in Duffy positive subjects 16ng/mL as compared to Duffy negative subjects (7ng/mL p

Description: Background: Antithrombin (AT) had beneficial effects on mortality of septic patients in an a priori defined subpopulation of the Kypersept trial, which received no concomitant administration of heparin. Objectives: We hypothesized that recombinant human (rh)AT (without concomitant heparin) has anticoagulant properties and may decrease cytokine production in a well standardized model of human endotoxemia. Methods: This study was randomized, double-blind, placebo-controlled in parallel groups in 30 healthy male volunteers. The active treatment groups received bolus primed continuous infusion of rhAT (recombinant human Antithrombin) to increase AT-levels to 200% and 500% iv. before infusion of 2ng/kg endotoxin Results: Infusion of rhAT rapidly decreased neutrophil (p

Description: Background: BIBT 986 is a novel potent anticoagulant that dually inhibits Factors Xa and IIa. We hypothesized that BIBT 986 would dose-dependently decrease endotoxin-induced, tissue factor triggered coagulation activation. Hence it was the aim of the study to compare with placebo the anticoagulant activity of three dosages of BIBT 986 on parameters of coagulation, platelet activation and inflammation and to examine the safety of BIBT 986 in this setting. Methods: This study was a prospective, randomized, double-blind, placebo-controlled, parallel-group dose escalation trial in 48 healthy male volunteers. Participants were randomised to receive bolus primed continuous infusions of one of the three doses of BIBT 986 or placebo. All of them received a bolus infusion of 2ng/kg body weight lipopolysaccharide (LPS). Results: BIBT dose-dependently increased anti-Xa activity, activated partial thromboplastin time (APTT), ecarin clotting time (ECT), thrombin time (TT) and the international normalisation ratio (INR). Importantly, BIBT 986 dose-dependently blocked the LPS-induced coagulation as assessed by the in vivo markers of thrombin generation and action: BIBT 986 doses that prolonged APTT by 25% were already effective. The BIBT dose that prolonged APTT by 100%, completely suppressed the increase in prothrombin fragment (F1+2), thrombin-antithrombin complexes (TAT) and D-dimer. BIBT 986 had no influence on activation markers of inflammation, fibrinolysis, endothelial or platelet activation. Conclusion: Infusion of BIBT 986 was safe and well tolerated. BIBT 986 specifically and dose-dependently blocked LPS-induced, tissue factor trigger coagulation. When compared to different anticoagulants tested previously in this standardized model, BIBT 986 was more effective in suppressing thrombin generation (F1+2 levels) than standard doses of danaparoid, dalteparin or lepirudin. BIBT 986 represents the first drug of a new class of dual FXa and FIIa inhibitors, and displays high potency.

Description: Background: ARC1779 is an aptamer which blocks the binding of the vWF A1 domain to platelet GPIb receptors. In TTP there is an excess of ultra-large multimers of vWF which are especially avid for binding GPIb and give rise to disseminated platelet thrombi which are fibrin-poor and vWF-rich in composition. ARC1779 is being evaluated for use as front-line therapy of acute TTP in conjunction with plasma exchange. ARC1779 has already been demonstrated in healthy volunteers to inhibit vWF activity and vWF-dependent platelet function. ARC1779 has no anticoagulant effect and does not inhibit other pathways of platelet activation. ARC1779 is expected to normalize platelet dysfunction and prevent the thrombotic end-organ complications of TTP based upon the mechanism of action defined for ARC1779 and the mechanism of thrombosis defined for TTP. Methods: We first assessed vWF activity (vWF:RiCO) and platelet function in blood samples taken from TTP patients and age-matched, healthy controls. We then studied the ex vivo dose response curves for ARC1779 on vWF activity (free A1 domain sites) and on platelet function assessed by the Platelet Function Analyzer (PFA-100®), cone and plate analyzer (IMPACT®), and agonist-induced impedence platelet aggregometry (Multiplate®) of TTP patients (N=10, 2 in acute phase and 8 in remission) and healthy age-matched controls (N=23). Results: vWF:RiCO activity (p=0.002) and vWF-dependent platelet plug formation (p=0.001) were increased in TTP patients relative to healthy controls, but agonist-induced platelet aggregation (ADP, arachidonic acid, collagen, TRAP) was not. ARC1779 fully blocked platelet plug formation as measured by PFA-100® with an IC100 of ∼ 1 mcg/mL with citrate anticoagulation, and ∼ 3–4 mcg/mL with hirudin anticoagulation in both TTP patients and in healthy controls. ARC1779 fully blocked shear-dependent platelet adhesion measured by the IMPACT® analyzer with an IC100 of ∼ 1 mcg/mL with citrate anticoagulation in both TTP patients and in healthy controls. ARC1779 fully blocked vWF activity (free A1 domain sites) with an IC90 of ∼ 6 mcg/mL in TTP patients and ∼ 2 mcg/mL in young controls (p