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

2014 ◽  
Vol 34 (5) ◽  
pp. 845-851 ◽  
Author(s):  
Adel Helmy ◽  
Mathew R Guilfoyle ◽  
Keri LH Carpenter ◽  
John D Pickard ◽  
David K Menon ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Receptor Antagonist ◽  
Phase Ii ◽  
Interleukin 1 ◽  
Safety Data ◽  
Extracellular Fluid ◽  
Cerebral Microdialysis ◽  
Interleukin 1 Receptor Antagonist ◽  
Randomized Control

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 rh I Lira-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.

CEREBROSPINAL FLUID INTERLEUKIN-1 RECEPTOR ANTAGONIST FOLLOWING SEVERE TRAUMATIC BRAIN INJURY

Shock ◽  
2006 ◽  
Vol 26 (Supplement 1) ◽  
pp. 21
Author(s):  
V. Bogner ◽  
P. Biberthaler ◽  
S. Buhmann ◽  
J. Stegmaier ◽  
K.G. Kanz ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cerebrospinal Fluid ◽  
Brain Injury ◽  
Receptor Antagonist ◽  
Severe Traumatic Brain Injury ◽  
Interleukin 1 ◽  
Interleukin 1 Receptor Antagonist

scholarly journals The Cytokine Response to Human Traumatic Brain Injury: Temporal Profiles and Evidence for Cerebral Parenchymal Production

2010 ◽  
Vol 31 (2) ◽  
pp. 658-670 ◽  
Author(s):  
Adel Helmy ◽  
Keri LH Carpenter ◽  
David K Menon ◽  
John D Pickard ◽  
Peter JA Hutchinson
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Plasma Concentrations ◽  
Extracellular Fluid ◽  
Cd40 Ligand ◽  
Cerebral Microdialysis ◽  
Soluble Cd40 Ligand ◽  
Diverse Range

The role of neuroinflammation is increasingly being recognised in a diverse range of cerebral pathologies, including traumatic brain injury (TBI). We used cerebral microdialysis and paired arterial and jugular bulb plasma sampling to characterise the production of 42 cytokines after severe TBI in 12 patients over 5 days. We compared two microdialysis perfusates in six patients: central nervous system perfusion fluid and 3.5% human albumin solution (HAS); 3.5% HAS has a superior fluid recovery (95.8 versus 83.3%), a superior relative recovery in 18 of 42 cytokines (versus 8 of 42), and a qualitatively superior recovery profile. All 42 cytokines were recovered from the human brain. Sixteen cytokines showed a stereotyped temporal peak, at least twice the median value for that cytokine over the monitoring period; day 1: tumour necrosis factor, interleukin (IL)7, IL8, macrophage inflammatory protein (MIP)1α, soluble CD40 ligand, GRO, IL1β, platelet derived growth factor (PDGF)-AA, MIP1β, RANTES; day 2: IL1 receptor antagonist (ra). IL6, granulocyte-colony stimulating factor (G-CSF), chemokine CXC motif ligand 10 (IP10); days 4 to 5: IL12p70, IL10. Brain extracellular fluid concentrations were significantly higher than plasma concentrations for 19 cytokines: basic fibroblast growth factor (FGF2), G-CSF, IL1α, IL1 β, IL1ra, IL3, IL6, IL8, IL10, IL12p40, IL12p70, IP10, monocyte chemotactic protein (MCP)1, MCP3, MIP1α, MIP1β, PDGF-AA, transforming growth factor (TGF)α and vascular endothelial growth factor. No clear arterio-jugular venous gradients were apparent. These data provide evidence for the cerebral production of these cytokines and show a stereotyped temporal pattern after TBI.

scholarly journals Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

2012 ◽  
Vol 32 (9) ◽  
pp. 1810-1819 ◽  
Author(s):  
Jesus M Pradillo ◽  
Adam Denes ◽  
Andrew D Greenhalgh ◽  
Herve Boutin ◽  
Caroline Drake ◽  
...  
Keyword(s):  
Risk Factors ◽  
Brain Injury ◽  
Receptor Antagonist ◽  
Brain Damage ◽  
Infarct Volume ◽  
Interleukin 1 ◽  
Experimental Stroke ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Interleukin 1 Receptor Antagonist

Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90 minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25 mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24 hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood–brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke.

scholarly journals Attenuation of Stroke Size in Rats Using an Adenoviral Vector to Induce Overexpression of Interleukin-1 Receptor Antagonist in Brain

1995 ◽  
Vol 15 (4) ◽  
pp. 547-551 ◽  
Author(s):  
A. Lorris Betz ◽  
Guo-Yuan Yang ◽  
Beverly L. Davidson
Keyword(s):  
Brain Injury ◽  
Receptor Antagonist ◽  
Recombinant Adenovirus ◽  
Infarct Volume ◽  
Interleukin 1 ◽  
Adenovirus Vector ◽  
Histochemical Staining ◽  
Artery Occlusion ◽  
Central Administration ◽  
Interleukin 1 Receptor Antagonist

Adenoviruses have been proposed as potential vectors for gene therapy in the central nervous system, but there are no reports of their use in the treatment of a brain disease. Because central administration of interleukin-1 receptor antagonist protein (IL-1ra) reduces ischemic brain damage, we determined whether a recombinant adenovirus vector carrying the human IL-1ra cDNA (Ad.RSV IL-1ra) could be used to ameliorate brain injury in permanent focal ischemia. Groups of six rats received intraventricular injections of Ad.RSV IL-1ra or a control adenovirus containing the Escherichia coli β-galactosidase gene (Ad.RSV lacZ). Histochemical staining for β-galactosidase 5 days after virus injection indicated that transgene expression was confined primarily to the cells lining the ventricle. The concentrations of IL-1ra were fivefold to 50-fold higher in the Ad.RSV IL-1ra-injected animals, achieving levels of 9.1 ± 3.3 ng/g in brain and 23.7 ± 22.5 ng/ml in CSF. In these animals, cerebral infarct volume resulting from 24 h of permanent middle cerebral artery occlusion was reduced 64%. These studies demonstrate that adenoviral vectors can be used to deliver genes that attenuate brain injury.

Hypoxia-ischemia in immature rats: Interleukin-1 receptor antagonist reduces brain injury

1997 ◽  
Vol 176 (1) ◽  
pp. S170
Author(s):  
H. Hagberg ◽  
E. Gilland ◽  
E. Bona ◽  
L-Å Hanson ◽  
M. Hahn-Zoric ◽  
...  
Keyword(s):  
Brain Injury ◽  
Receptor Antagonist ◽  
Interleukin 1 ◽  
Interleukin 1 Receptor Antagonist ◽  
Immature Rats ◽  
Hypoxia Ischemia

scholarly journals Interleukin-1 Receptor Antagonist Penetrates Human Brain at Experimentally Therapeutic Concentrations

2007 ◽  
Vol 28 (2) ◽  
pp. 387-394 ◽  
Author(s):  
Simon R Clark ◽  
Catherine J McMahon ◽  
Iva Gueorguieva ◽  
Malcolm Rowland ◽  
Sylvia Scarth ◽  
...  
Keyword(s):  
Brain Injury ◽  
Receptor Antagonist ◽  
Cerebral Ischaemia ◽  
Interleukin 1 ◽  
Therapeutic Benefit ◽  
Focal Cerebral Ischaemia ◽  
Interleukin 1 Receptor Antagonist ◽  
Ischaemic Brain ◽  
Steady State Plasma Concentration ◽  
The Brain

The proinflammatory cytokine interleukin (IL)-1 mediates several forms of experimentally induced acute brain injury and has been implicated in chronic neurodegenerative disorders. The IL-1 receptor antagonist, IL-1RA, protects rodents against ischaemic brain injury, but its molecular mass (17 kDa) potentially limits the brain penetration of peripherally administered IL-1RA. We therefore sought to identify whether therapeutically effective concentrations of IL-1RA in the rat were also achieved in brain of patients with subarachnoid haemorrhage (SAH), using a peripheral administration regime that had proved to be safe and reduce peripheral inflammation in patients after stroke. An intravenous bolus of IL-1RA, followed by infusion, was administered to rats after induction of focal cerebral ischaemia. The effects of IL-1RA on brain ischaemia and the concentrations achieved in cerebrospinal fluid (CSF), were determined. Interleukin-1 receptor antagonist was similarly administered to patients with SAH, and CSF was sampled via external ventricular drains. In rats, IL-1RA significantly reduced brain injury induced by focal cerebral ischaemia. The plasma IL-1RA concentrations reached 12±2 μg/mL by 30 mins, and CSF concentrations were maintained between 91 and 232 ng/mL between 1 and 24 h of infusion. In patients with SAH, IL-1RA reached a steady-state plasma concentration of 22 ± 4 μg/mL by 15 mins, and CSF concentrations were maintained at 78 to 558 ng/mL between 1 and 24 h. Intravenous delivery of IL-1RA leads to CSF concentrations in patients comparable to those that are neuroprotective in rats, and might therefore be of therapeutic benefit.

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