Confirmatory interleukin-1 receptor antagonist trial in severe sepsis

Opal, Steven M.; Fisher, Charles J.; Dhainaut, Jean-François; Vincent, Jean‐Louis; Brase, Rainer; Lowry, Stephen F.; Sadoff, Jerald C.; Slotman, Gus J.; Levy, Howard; Balk, R.A.; Shelly, M. P.; Pribble, John P.; LaBrecque, J.F.; Lookabaugh, Janice L.; Donovan, Heidi; Dubin, Howard V.; Baughman, Robert P.; Norman, James; DeMaria, Eric J.; Matzel, Klaus E.; Abraham, Edward; Seneff, Michael G.

doi:10.1097/00003246-199707000-00010

Cited by 765 publications

(183 citation statements)

References 30 publications

Supporting

Mentioning

177

Contrasting

Unclassified

Order By: Relevance

“…These data suggest that attempts to block IL-1 activity as an adjunctive treatment of septic complications in patients with obstructive jaundice may be more successful than anticipated from the negative data derived from clinical trials with recombinant IL-1 receptor antagonist after general sepsis. 41,42 To date, understanding of the role of inflammatory mediators in the increased endotoxin sensitivity during cholestasis is limited. TNF is known to be involved in the changes in body temperature in response to endotoxin in cholestatic rats.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1 receptor type I gene-deficient bile duct-ligated mice are partially protected against endotoxin

et al. 2002

View full text Add to dashboard Cite

Cholestatic liver injury is associated with an increased susceptibility toward endotoxininduced toxicity. To determine the role of interleukin 1 (IL-1) herein, extrahepatic cholestasis was induced by bile duct ligation (bdl) in IL-1 receptor type I gene-deficient (IL-1R ؊/؊ ) mice, which are unresponsive to IL-1␣ and IL-1␤, and normal IL-1R ؉/؉ mice. Bdl elicited increases in hepatic IL-1␣ and IL-1␤ messenger RNA (mRNA) and protein. Hepatocellular injury at 2 weeks after bdl was similar in IL-1R ؊/؊ and IL-1R ؉/؉ mice as shown by clinical chemistry and histopathology. Administration of endotoxin to cholestatic mice at 2 weeks after bdl was associated with enhanced cytokine release, more severe liver damage, and occurrence of death when compared with sham-operated mice. Endotoxin effects in shamoperated IL-1R ؊/؊ and IL-1R ؉/؉ mice were largely similar, but cholestatic IL-1R ؊/؊ mice were better protected against toxic effects of endotoxin, as reflected by lowered cytokine release, less profound liver injury, and reduced mortality. These data indicate that IL-1␣ and IL-1␤ are produced in the liver after bdl, but that these cytokines do not play a significant role in cholestatic liver damage; however, endogenous IL-1 activity is an important denominator of enhanced endotoxin sensitivity that is observed during cholestasis induced by bdl. S urgery in jaundiced patients with periampullary tumors carries an increased risk of postoperative complications. 1 Whereas in experienced centers, postoperative mortality has been reduced from 20% to 5%, morbidity remains as high as 50%. 2,3 Most complications have a septic etiology and are considered to be related with translocation of endotoxin from the intestinal lumen into the portal and systemic circulation where an inflammatory cascade is triggered. 4,5 Potential causes of translocation of endotoxin include lack of bile salts in the intestinal lumen resulting in increased bacterial translocation, 6,7 decreased function of the resident macrophages of the liver (the Kupffer cells) leading to inadequate interception of endotoxin, 6-8 and changes in plasma concentrations of lipoproteins which bind endotoxin. 9 In addition, cholestasis is associated with enhanced susceptibility toward endotoxin-induced toxicity. [9][10][11][12][13][14] Endotoxin exerts its biological effects by activating immunocompetent cells such as monocytes and macrophages. After exposure to endotoxin, these cells readily release various inflammatory mediators such as the cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1), 15 which leads to an inflammatory response. The Kupffer cells are also capable of releasing these cytokines in response to endotoxin. 16,17 IL-1␣ and IL-1␤ are pleiotropic proinflammatory cytokines that are considered to play a proximal role in initiation and regulation of the inflammatory cascade triggered in response to endotoxins or bacteremia. 15,18 Both IL-1␣ and IL-1␤ can interact with two specific cell surface receptors, the type I and type II IL-1 receptor (IL-1R), of ...

show abstract

Section: Discussionmentioning

confidence: 99%

Interleukin-1 receptor type I gene-deficient bile duct-ligated mice are partially protected against endotoxin

et al. 2002

View full text Add to dashboard Cite

show abstract

“…11 This dose and route of administration was utilized as hrIL1ra, has a well-defined safety profile, and has previously been trialled in stroke, 12 subarachnoid hemorrhage, 13,14 and severe sepsis. 15 We have used our previously validated cerebral microdialysis methodology 16,17 with a combination of arterial plasma sampling predosing and postdosing ( Figure 1) to provide a comprehensive biochemical assessment of the consequences of IL1R antagonism after human TBI and have analyzed the resulting high-dimensional data sets with multivariate projection methods. 18 …”

Section: Traumatic Brain Injury (Tbi)mentioning

confidence: 99%

Recombinant Human Interleukin-1 Receptor Antagonist in Severe Traumatic Brain Injury: A Phase II Randomized Control Trial

Helmy

Guilfoyle

Carpenter

et al. 2014

J Cereb Blood Flow Metab

147

169

View full text Add to dashboard Cite

Traumatic brain injury (TBI) is the commonest cause of death and disability in those aged under 40 years. Interleukin-1 receptor antagonist (IL1ra) is an endogenous competitive antagonist at the interleukin-1 type-1 receptor (IL-1R). Antagonism at the IL-1R confers neuroprotection in several rodent models of neuronal injury (i.e., trauma, stroke and excitotoxicity). We describe a single center, phase II, open label, randomized-control study of recombinant human IL1ra (rhIL1ra, anakinra) in severe TBI, at a dose of 100 mg subcutaneously once a day for 5 days in 20 patients randomized 1:1. We provide safety data (primary outcome) in this pathology, utilize cerebral microdialysis to directly determine brain extracellular concentrations of IL1ra and 41 cytokines and chemokines, and use principal component analysis (PCA) to explore the resultant cerebral cytokine profile. Interleukin-1 receptor antagonist was safe, penetrated into plasma and the brain extracellular fluid. The PCA showed a separation in cytokine profiles after IL1ra administration. A candidate cytokine from this analysis, macrophage-derived chemoattractant, was significantly lower in the rhIL1ra-treated group. Our results provide promising data for rhIL1ra as a therapeutic candidate by showing safety, brain penetration and a modification of the neuroinflammatory response to TBI by a putative neuroprotective agent in humans for the first time.

show abstract

“…In the 1980s and 1990s, multiple therapies targeting proinflammatory mediators and aimed at reducing inflammation reached phase III clinical trials in adults with severe sepsis and septic shock [1][2][3][4][5][6][7][8][9][10][11][12]. Nearly all of these studies failed to demonstrate a survival benefit, suggesting that perhaps reducing inflammation is not the appropriate therapeutic goal in all cases.…”

Section: Introductionmentioning

confidence: 99%