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DewDiligence

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Re: DewDiligence post# 18342

Wednesday, 01/18/2006 11:04:09 PM

Wednesday, January 18, 2006 11:04:09 PM

Post# of 252302
Another ATryn study from the Medical U of Vienna:

[Please see #msg-8452794 and #msg-7268415 for prior ATryn studies from this team of investigators.]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_...

>>
Clin Pharmacol Ther. 2006 Jan;79(1):23-34.

Recombinant human antithrombin inhibits thrombin formation and interleukin 6 release in human endotoxemia.

Leitner JM, Firbas C, Mayr FB, Reiter RA, Steinlechner B, Jilma B.

Department of Clinical Pharmacology, Division of Immunohaematology, Medical University of Vienna, Austria; Department of Anaesthesia and Intensive Care Medicine, Medical University of Vienna, Austria.

We hypothesized that infusion of recombinant human antithrombin without concomitant heparin would have dose-dependent anticoagulant properties and potentially decrease endotoxin (lipopolysaccharide [LPS])-induced cytokine production. This was a randomized, double-blind, placebo-controlled study in parallel groups enrolling 30 healthy male volunteers. The active treatment groups received infusions of recombinant human antithrombin to increase antithrombin levels to 200% and 500% before infusion of 2 ng/kg endotoxin (LPS).

Infusion of antithrombin dose-dependently decreased coagulation (P < .01 by repeated-measures ANOVA): peak levels of prothrombin fragment (1.8 nmol/L [95% confidence interval (CI), 1.3-2.3 nmol/L] in the 500% antithrombin group and 4.4 nmol/L [95% CI, 2.7-6.2 nmol/L] in the placebo group at 4 hours), thrombin antithrombin complexes (12 mug/L [95% CI, 8-16 mug/L] in the 500% antithrombin group and 34 mug/L [95% CI, 20-48 mug/L] in the placebo group at 4 hours), and D-dimer (0.2 mug/L [95% CI, 0.1-0.2 mug/L] in the 500% antithrombin group and 0.5 mug/L [95% CI, 0.4-0.7 mug/L] in the placebo group). Recombinant human antithrombin decreased peak interleukin-6 levels by 40% (222 pg/mL [95% CI, 148-295 pg/mL] and 216 pg/mL [95% CI, 112-320 pg/mL] in the 500% and 200% antithrombin groups, respectively, versus 357 pg/mL [95% CI, 241-474 pg/mL] in the placebo group; P < .001 by ANOVA). Finally, infusion of recombinant human antithrombin rapidly and transiently decreased neutrophil counts (by 19% [95% CI, 8%-30%] in the 500% antithrombin group versus 6% [95% CI, 1%-10%] in the placebo group, P = .002 by Kruskal-Wallis ANOVA) and monocyte counts (by 30% [95% CI, 16%-44%] in the 500% antithrombin group and 18% [95% CI, 9%-28%] in the 200% antithrombin group versus 8% [95% CI, 5%-20%] in the placebo group, P = .04) before LPS challenge, indicating that recombinant human antithrombin directly interacts with these leukocyte subsets.

In summary, recombinant human antithrombin dose-dependently inhibited tissue factor-triggered coagulation. Effects on leukocytes and inhibition of interleukin-6 release seem to represent specific pharmacodynamic properties of recombinant human antithrombin.
<<

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