James Galea

The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II randomised controlled trial

BackgroundInterleukin-1 (IL-1) is a key mediator of ischaemic brain injury induced by stroke and subarachnoid haemorrhage (SAH). IL-1 receptor antagonist (IL-1Ra) limits brain injury in experimental stroke and reduces plasma inflammatory mediators associated with poor outcome in ischaemic stroke patients. Intravenous (IV) IL-1Ra crosses the blood–brain barrier (BBB) in patients with SAH, to achieve cerebrospinal fluid (CSF) concentrations that are neuroprotective in rats.MethodsA small phase II, double-blind, randomised controlled study was carried out across two UK neurosurgical centres with the aim of recruiting 32 patients. Adult patients with aneurysmal SAH, requiring external ventricular drainage (EVD) within 72 hours of ictus, were eligible. Patients were randomised to receive IL-1Ra (500 mg bolus, then a 10 mg/kg/hr infusion for 24 hours) or placebo. Serial samples of CSF and plasma were taken and analysed for inflammatory mediators, with change in CSF IL-6 between 6 and 24 hours as the primary outcome measure.ResultsSix patients received IL-1Ra and seven received placebo. Concentrations of IL-6 in CSF and plasma were reduced by one standard deviation in the IL-1Ra group compared to the placebo group, between 6 and 24 hours, as predicted by the power calculation. This did not reach statistical significance (P = 0.08 and P = 0.06, respectively), since recruitment did not reach the target figure of 32. No adverse or serious adverse events reported were attributable to IL-1Ra.ConclusionsIL-1Ra appears safe in SAH patients. The concentration of IL-6 was lowered to the degree expected, in both CSF and plasma for patients treated with IL-1Ra.

Intravenous anakinra can achieve experimentally effective concentrations in the central nervous system within a therapeutic time window: results of a dose-ranging study

The naturally occurring antagonist of interleukin-1, IL-1RA, is highly neuroprotective experimentally, shows few adverse effects, and inhibits the systemic acute phase response to stroke. A single regime pilot study showed slow penetration into cerebrospinal fluid (CSF) at experimentally therapeutic concentrations. Twenty-five patients with subarachnoid hemorrhage (SAH) and external ventricular drains were sequentially allocated to five administration regimes, using intravenous bolus doses of 100 to 500 mg and 4 hours intravenous infusions of IL-1RA ranging from 1 to 10 mg per kg per hour. Choice of regimes and timing of plasma and CSF sampling was informed by pharmacometric analysis of pilot study data. Data were analyzed using nonlinear mixed effects modeling. Plasma and CSF concentrations of IL-1RA in all regimes were within the predicted intervals. A 500-mg bolus followed by an intravenous infusion of IL-1RA at 10 mg per kg per hour achieved experimentally therapeutic CSF concentrations of IL-1RA within 45 minutes. Experimentally, neuroprotective CSF concentrations in patients with SAH can be safely achieved within a therapeutic time window. Pharmacokinetic analysis suggests that IL-1RA transport across the blood–CSF barrier in SAH is passive. Identification of the practicality of this delivery regime allows further studies of efficacy of IL-1RA in acute cerebrovascular disease.

Rapid brain penetration of interleukin‐1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics, distribution, protection

Background and purpose:  Limited data on the brain penetration of potential stroke treatments have been cited as a major weakness contributing to numerous failed clinical trials. Thus, we tested whether interleukin‐1 receptor antagonist (IL‐1RA), established as a potent inhibitor of brain injury in animals and currently in clinical development, reaches the brain via a clinically relevant administration route, in experimental stroke.

[18F]DPA-714: Direct Comparison with [11C]PK11195 in a Model of Cerebral Ischemia in Rats

Purpose Neuroinflammation is involved in several brain disorders and can be monitored through expression of the translocator protein 18 kDa (TSPO) on activated microglia. In recent years, several new PET radioligands for TSPO have been evaluated in disease models. [18F]DPA-714 is a TSPO radiotracer with great promise; however results vary between different experimental models of neuroinflammation. To further examine the potential of [18F]DPA-714, it was compared directly to [11C]PK11195 in experimental cerebral ischaemia in rats. Methods Under anaesthesia, the middle cerebral artery of adult rats was occluded for 60 min using the filament model. Rats were allowed recovery for 5 to 7 days before one hour dynamic PET scans with [11C]PK11195 and/or [18F]DPA-714 under anaesthesia. Results Uptake of [11C]PK11195 vs [18F]DPA-714 in the ischemic lesion was similar (core/contralateral ratio: 2.84±0.67 vs 2.28±0.34 respectively), but severity of the brain ischemia and hence ligand uptake in the lesion appeared to vary greatly between animals scanned with [11C]PK11195 or with [18F]DPA-714. To solve this issue of inter-individual variability, we performed a direct comparison of [11C]PK11195 and [18F]DPA-714 by scanning the same animals sequentially with both tracers within 24 h. In this direct comparison, the core/contralateral ratio (3.35±1.21 vs 4.66±2.50 for [11C]PK11195 vs [18F]DPA-714 respectively) showed a significantly better signal-to-noise ratio (1.6 (1.3–1.9, 95%CI) fold by linear regression) for [18F]DPA-714. Conclusions In a clinically relevant model of neuroinflammation, uptake for both radiotracers appeared to be similar at first, but a high variability was observed in our model. Therefore, to truly compare tracers in such models, we performed scans with both tracers in the same animals. By doing so, our result demonstrated that [18F]DPA-714 displayed a higher signal-to-noise ratio than [11C]PK11195. Our results suggest that, with the longer half-life of [18F] which facilitates distribution of the tracer across PET centre, [18F]DPA-714 is a good alternative for TSPO imaging.

The intrathecal CD163-haptoglobin-hemoglobin scavenging system in subarachnoid hemorrhage.

J. Neurochem. (2012) 121, 785–792.

Cerebrospinal fluid and plasma cytokines after subarachnoid haemorrhage: CSF interleukin-6 may be an early marker of infection

AbstractBackgroundCytokines and cytokine receptor concentrations increase in plasma and cerebrospinal fluid (CSF) of patients following subarachnoid haemorrhage (SAH). The relationship between plasma and CSF cytokines, and factors affecting this, are not clear.MethodsTo help define the relationship, paired plasma and cerebrospinal fluid (CSF) samples were collected from patients subject to ventriculostomy. Concentrations of key inflammatory cytokines, interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1Ra), IL-1 receptor 2, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, and TNF receptors (TNF-R) 1 and 2 were determined by immunoassay of CSF and plasma from 21 patients, where samples were available at three or more time points.ResultsPlasma concentrations of IL-1ß, IL-1Ra, IL-10, TNF-α and TNF-R1 were similar to those in CSF. Plasma TNF-R2 and IL-1R2 concentrations were higher than in CSF. Concentrations of IL-8 and IL-6 in CSF were approximately10 to 1,000-fold higher than in plasma. There was a weak correlation between CSF and plasma IL-8 concentrations (r = 0.26), but no correlation for IL-6. Differences between the central and peripheral pattern of IL-6 were associated with episodes of ventriculostomy-related infection (VRI). A VRI was associated with CSF IL-6 >10,000 pg/mL (P = 0.0002), although peripheral infection was not significantly associated with plasma IL-6.ConclusionsThese data suggest that plasma cytokine concentrations cannot be used to identify relative changes in the CSF, but that measurement of CSF IL-6 could provide a useful marker of VRI.

The role of inflammation and interleukin-1 in acute cerebrovascular disease

Acute cerebrovascular disease can affect people at all stages of life, from neonates to the elderly, with devastating consequences. It is responsible for up to 10% of deaths worldwide, is a major cause of disability, and represents an area of real unmet clinical need. Acute cerebrovascular disease is multifactorial with many mechanisms contributing to a complex pathophysiology. One of the major processes worsening disease severity and outcome is inflammation. Pro-inflammatory cytokines of the interleukin (IL)-1 family are now known to drive damaging inflammatory processes in the brain. The aim of this review is to discuss the recent literature describing the role of IL-1 in acute cerebrovascular disease and to provide an update on our current understanding of the mechanisms of IL-1 production. We also discuss the recent literature where the effects of IL-1 have been targeted in animal models, thus reviewing potential future strategies that may limit the devastating effects of acute cerebrovascular disease.

External ventricular drain infection: Improved technique can reduce infection rates

Abstract Introduction. The placement of external ventricular drain (EVD) is a common neurosurgical procedure to drain cerebrospinal fluid (CSF) in many acute neurosurgical conditions that disrupt the normal CSF absorption pathway. Infection is the primary complication with infection rates ranging between 0% and 45%, and this is associated with significant morbidity and mortality, prolonged hospital stay and increased hospital costs.This article compares and discusses the differences in rates of EVD CSF infection between clinical neurosurgical practice and the infection rates in a group of research patients where EVDs were sampled frequently as part of the study. Materials and methods. Patients who had EVD placed were identified by review of theatre logs from 2005–2008. A retrospective case-note review was performed with the primary end point being those patients treated with intrathecal antibiotics. Patients within the research group were identified from established data and the same primary endpoint was used. A standard silicone catheter was the EVD used in both cohorts. Patients were excluded if the EVD was placed for diagnoses other than hydrocephalus associated with aneurysmal subarachnoid haemorrhage (SAH). Results. Ninety-four patients had 156 EVDs placed within the clinical group, 49 patients were treated giving an infection rate within this group of 52.1% per patient and 31.4% per EVD. Thirty-nine patients had 39 EVDs placed within the research group, four patients were treated, the infection rate within this group was 10.3% per EVD, p = 0.0001. Conclusion. Sampling or irrigating ventricular drainage systems does not increase the risk of CNS infection providing the operator has appropriate experience and has used theatre standard aseptic technique.

Heme–Hemopexin Scavenging Is Active in the Brain and Associates With Outcome After Subarachnoid Hemorrhage

Background and Purpose— Long-term outcome after subarachnoid hemorrhage (SAH) is potentially linked to cytotoxic heme. Free heme is bound by hemopexin and rapidly scavenged by CD91. We hypothesized that heme scavenging in the brain would be associated with outcome after hemorrhage. Methods— Using cerebrospinal fluid and tissue from patients with SAH and control individuals, the activity of the intracranial CD91–hemopexin system was examined using ELISA, ultrahigh performance liquid chromatography, and immunohistochemistry. Results— In control individuals, cerebrospinal fluid hemopexin was mainly synthesized intrathecally. After SAH, cerebrospinal fluid hemopexin was high in one third of cases, and these patients had a higher probability of delayed cerebral ischemia and poorer neurological outcome. The intracranial CD91–hemopexin system was active after SAH because CD91 positively correlated with iron deposition in brain tissue. Heme–hemopexin uptake saturated rapidly after SAH because bound heme accumulated early in the cerebrospinal fluid. When the blood–brain barrier was compromised after SAH, serum hemopexin level was lower, suggesting heme transfer to the circulation for peripheral CD91 scavenging. Conclusions— The CD91–heme–hemopexin scavenging system is important after SAH and merits further study as a potential prognostic marker and therapeutic target.

Translational pharmacokinetics: challenges of an emerging approach to drug development in stroke

Introduction: There is increasing recognition of the importance of translational pharmacokinetics in stroke research, lack of which has been cited as one of the main contributing factors to failure of Phase III trials. Areas covered: The article reviews the translational issues in administration, distribution and sampling in the pharmacokinetics of putative therapeutic drugs in stroke. In addition, the role of translational pharmacometrics in drug development is discussed. The review uses the anti-inflammatory agent, IL-1 receptor antagonist, as an example. The reader will gain an insight into the pitfalls that are commonplace in translating pharmacokinetics from the preclinical to the clinical scenario. The reader will also gain an understanding of the complexities of blood–central nervous system (CNS) barriers in relation to brain pharmacokinetics and the increasing use of translational pharmacometrics in stroke research. Expert opinion: The translation of preclinical to clinical pharmacokinetics is a discipline that is traditionally overlooked and is likely to be a key factor responsible for failure of clinical trials. With a clear comprehensive insight into the benefits and limitations of translational pharmacokinetics in stroke, translational pharmacokinetics can be safely used to enhance the efficacy of clinical trials in stroke and their likelihood of success.