A randomized placebo-controlled trial in healthy volunteers examining the effects of acetaminophen and NO-acetaminophen NCX 701 in human endotoxemia

The development of nitric oxide-donating antiphlogistics is intended to improve the tolerability of the parent compounds. The aim of the present study was to explore the potency and tolerability of nitric oxide-donating acetaminophen (NCX 701) in healthy volunteers and to test the hypothesis that NCX 701 could have additional anti-inflammatory efficacy in an experimental model of low-grade human endotoxemia. In this prospective, double-blind, placebo-controlled trial with parallel group design 40 healthy male volunteers were randomized to single oral treatment with NCX 701 (1-2 g), acetaminophen (1 g paracetamol) or placebo before lipopolysaccharide (2ng/kg) infusion. NCX 701 dose-dependently increased plasma and urine nitric oxide concentrations. Pooled analysis of both NCX 701 doses showed a significant, but obviously clinically irrelevant lowering effect on systolic and diastolic blood pressure during the first 5 h. Overall, peak levels of tumor necrosis factor-alpha correlated well with interleukin-6, interleukin-8, monocyte chemoattractant protein-1 and von Willebrand Factor release across all cohorts. There was no major difference between NCX 701 and acetaminophen with respect to their effect on the lipopolysaccharide-induced secretion of inflammation and endothelium activation markers. Overall, a total of 61 adverse events were reported in all treatment arms, mainly related to lipopolysaccharide. Both acetaminophen and NCX 701 effectively reduced the proportion of subjects experiencing headache. Despite substantial nitric oxide release by NCX 701, which reduced arterial blood pressure, nitric oxide did not result in relevant inhibition of lipopolysaccharide-induced inflammation.ISRCTN registry number: ISTCTN-13,358,268.