Xenon in Medicine
Xenon (symbol: Xe) is a noble gas, without haemodynamic instability which is widely used in medicine and has a history of use as an anaesthetic in Europe since 2007. Xenon is also a potent neurological protectant which prevents brain cells from dying during a hypoxic-ischaemic event (lack of blood flow) and other acute ongoing neurological injuries.
A landmark discovery by NeuroproteXeon co-founder, Professor Nick Franks revealed xenon to be a potent N-methyl-D-aspartate (NMDA) receptor antagonist.
Xenon is known to have several mechanisms of action for its neuroprotective properties.
- Following a cardiac arrest there is a massive release of the excitatory neurotransmitter, glutamate in the brain. Xenon prevents the activation of the NMDA receptor ion channel via glutamate by competing with glycine for the NMDA receptor’s co-activation site. Therefore, the ion channel remains closed and the cascade of damaging effects as a result of cation (Ca2+ and Na+ ions) influx through the NMDA ion channel, is prevented.
- Xenon also activates TREK 1 and ATP-sensitive potassium channels (opening them) resulting in hyperpolarisation of the cell membrane and preventing the release of the excitatory neurotransmitter glutamate.
- Xenon also appears to have an indirect effect on erythropoietin (‘‘EPO’’). Xenon has been shown to boost the production of the transcription factor known as Hypoxia Inducible Factor HIF1 Alpha (HIF1a). HIF1a upregulates several genes intended to promote cellular survival in low-oxygen conditions, including EPO. While EPO originates primarily in the kidneys the brain has also been shown capable of producing it (perhaps given its sensitivity to ischaemia) and EPO membrane receptors and signalling pathways are prevalent in several different brain cell types. Specifically, EPO is involved in several signalling pathways that increase the brain’s resistance to ischaemia. It is responsible for stabilising mitochondrial membranes, limiting formation of free radical species (potentially reducing excitotoxicity) and suppressing pro-inflammatory cytokine production (such as IL-1 and TNF-alpha). In addition, EPO reduces leucocyte infiltration (which will further reduce inflammation) and promotes the expression of antiapoptotic proteins and thereby reduces activity in apoptotic pathways.
- Xenon also increases anti-apoptotic factors (such as BCI-2) and decreases apoptotic factors. These factors can play a neuroprotective role to Xenon’s actions.
Through these four mechanisms, it is thought that xenon interferes with several pathways and positive feedback loops that govern both the acute excitotoxic phase which results in cell necrosis; and, the medium to long term inflammation and apoptosis phase that leads to death of neurones.
Pre Clinical Trials
Since the discovery of xenon’s anaesthetic properties in the 1950s, many clinical trials have demonstrated its safety, including in patients with either brain or heart diseases. A landmark discovery by Neuroprotexeon co-founder, Professor Nick Franks (as published in Nature,1998), revealed xenon to be a potent NMDA receptor antagonist. The NMDA receptor is anion channel which plays a pivotal role in the development of acute ongoing neurological injury. Subsequently, pre-clinical studies have demonstrated that xenon is uniformly efficacious in various animal models of neuroprotection.
For more information see:
Preclinical neuroprotective actions of xenon and possible implications for human therapeutics: a narrative review. Maze, Canadian Journal of Anesthesia. February 2016, Volume 63, Issue 2, pp 212–226
The Phase II study, a 110-patient randomised clinical trial sought to establish whether the administration of xenon gas could prevent damage to the cerebral white brain matter (primary endpoint) as a result of a PCAS brain injury in humans. All patients in the trial were given the standard of care (targeted temperature management for 24 hours), half were supplemented by xenon gas and the remainder were not. The Phase II trial demonstrated a statistically significant reduction in brain tissue damage and a trend towards better survival outcomes in PCAS resulting from an Out of Hospital Cardiac Arrest (OHCA).
- The Primary Endpoint demonstrated a significant reduction in white brain matter damage (P=0.006), as measured by global fractional Anisotropy (GFA).
- GFA exhibited the best independent predictive value for mortality during the 6-month followup period.
- A Secondary Endpoint demonstrated a trend towards improved survival (P=0.053)
- The study was not powered to detect differences in these secondary endpoints
- A further Secondary Endpoint showed significant reduction of troponin T release during the first 72 hours (P=0.009)
The Results were reported in the Journal of the American Medical Association (‘‘JAMA’’). (March 2016 and Journal of the American College of Cardiology, November 2017)
In the Phase III trial, NPXe will further study differences in cardiac insult including its impact on good functioning and survival. They will also seek to determine if XENEX™ cardio-protective properties result in shorter ICU stays and related costs. Both FDA and EMA have agreed to a Special Protocol Agreement (SPA) for a Pivotal Phase III Trial. The FDA has also granted XENEXTM Fast Track.
- Size: 1,436 patients in over 70 sites in US and EU. (interim analysis at 718 patients)
- Patient Population: Patients who benefited the most in Phase II study (ROSC ≤ 30 minutes)
- Treatment: XENEX™ + Targeted Temperature Management (or “TTM”, cooling) vs. TTM alone
- Endpoints: Survival and Functional Outcome
- CRO: Cato Research will conduct the Phase III study
For more details, please visit clinicaltrials.gov