Ulla Derhaschnig

Summary: Reparixin, a CXCR 1/2 antagonist, has been shown to mitigate ischaemia–reperfusion injury (IRI) in various organ systems in animals, but data in humans are scarce. The aim of this double-blinded, placebo-controlled pilot study was to evaluate the safety and efficacy of reparixin to suppress IRI and inflammation in patients undergoing on-pump coronary artery bypass grafting (CABG). Patients received either reparixin or placebo (n = 16 in each group) after induction of anaesthesia until 8 h after cardiopulmonary bypass (CPB). We compared markers of systemic and pulmonary inflammation, surrogates of myocardial IRI and clinical outcomes using Mann–Whitney U- and Fisher's exact tests. Thirty- and 90-day mortality was 0% in both groups. No side effects were observed in the treatment group. Surgical revision, pleural and pericardial effusion, infection and atrial fibrillation rates were not different between groups. Reparixin significantly reduced the proportion of neutrophil granulocytes in blood at the beginning [49%, interquartile range (IQR) = 45–57 versus 58%, IQR = 53–66, P = 0·035], end (71%, IQR = 67–76 versus 79%, IQR = 71–83, P = 0·023) and 1 h after CPB (73%, IQR = 71–75 versus 77%, IQR = 72–80, P = 0·035). Reparixin patients required a lesser positive fluid balance during surgery (2575 ml, IQR = 2027–3080 versus 3200 ml, IQR = 2928–3778, P = 0·029) and during ICU stay (2603 ml, IQR = 1023–4288 versus 4200 ml, IQR = 2313–8160, P = 0·021). Numerically, more control patients required noradrenaline ≥ 0·11 μg/kg/min (50 versus 19%, P = 0·063) and dobutamine (50 versus 25%, P = 0·14). Therefore, administration of reparixin in CABG patients appears to be feasible and safe. It concurrently attenuated postoperative granulocytosis in peripheral blood.

Background Octaplas LG is a prion‐depleted version of a previous generation product called Octaplas S/D. We compared the recovery, safety, and tolerability of these two pharmaceutical‐grade plasmas. Study Design and Methods In this comparative, block‐randomized, open‐label, active‐controlled, crossover Phase I trial, 60 healthy adult volunteers received single transfusions of 1200 mL of parent product (in Period 1) and of the LG plasma product (in Period 2) or vice versa. In both periods, plasmapheresis (600 mL) preceded the transfusion. Blood samples were drawn before and after apheresis and 15 minutes, 2 hours, 24 hours, and 7 days after end of plasma transfusion, to assess recovery, safety, and tolerability. The primary efficacy endpoints were the changes in coagulation factors and hemostatic variables compared to baseline; their relative recovery was computed in the per‐protocol analysis (n = 43). Safety and tolerability were assessed (n = 60). Results Variations in coagulation factors and hemostatic variables over time were similar between the two treatments and within normal range; 90% confidence intervals for the derived recovery data were within predefined limits of equivalence. Both products were well tolerated. The advanced manufacturing process also significantly increased plasmin inhibitor concentrations after transfusion in vivo. Conclusion The LG plasma product was bioequivalent to its predecessor with respect to recovery of clotting factors and demonstrated comparable safety and tolerability in healthy volunteers. Both products compensated well for the loss of clotting factors after apheresis (NCT01063595).

Acute lung injury (ALI) and ARDS are difficult to manage and associated with substantial mortality. Suitable models are required in early clinical drug development to bridge the gap between preclinical experiments and clinical trials in severely ill patients. The aim of this trial was to validate bronchial endotoxin instillation as a model of early onset ALI by studying the anti-inflammatory and anti-edema effects of dexamethasone. We hypothesized that dexamethasone would decrease lung inflammation and ensuing vascular leakage. Twenty-four healthy young volunteers received dexamethasone twice (20mg iv. at -13h and -1h) in a randomized, double-blind, placebo controlled trial and volunteers had endotoxin (4 ng/kg) instilled into a lung segment and saline instilled into a contralateral segment at 0h, followed by bronchoalveolar lavage (BAL) at 6 h. Non-parametric statistical tests were applied. Endotoxin increased tumor necrosis factor levels from a median of 0.5 pg/mL 200-fold to 100 pg/mL in BAL samples (pConclusions: Dexamethasone effectively prevented LPS-induced vascular leakage and protein accumulation in the lung. Despite pronounced systemic anti-inflammatory effects, dexamethasone was comparably less effective in preventing IL-6 release from lung into BAL. The model lends itself for proof of concept studies of new drugs which target acute lung inflammation.

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