SCIENCE

XENON

Xenon in Medicine

Xenon (symbol: Xe) is a rare noble gas that has been historically used in the medical community for diagnostic and anesthetic purposes. A landmark discovery by NPXE’s founders revealed that xenon is a highly potent N-Methyl-D-aspartate receptor (NMDAR) antagonist with neuroprotective properties. Once inhaled, xenon binds to a unique site on the NMDAR and has been shown to regulate calcium channels and mitigate the negative effects of excessive calcium that leads to neuronal cell death in patients with compromised blood flow and poor oxygenation of brain tissue.

Xenon Mechanism of Action

Xenon’s multiple mechanisms of action and synergy with targeted temperature management (TTM), also known as therapeutic hypothermia, have been demonstrated to protect against neurologic injury in preclinical models.  Xenon’s mechanisms of action include:

  • Anti-Excitotoxicity – Anti-NMDA properties prevent excessive entry of calcium, a precursor to cell death early following several forms of acute neurological injury
  • Anti-Neuroapoptosis – Reduces expression of genes associated with programmed cell death (apoptosis) & increases anti-apoptotic proteins after neuronal injury
  • Cytotoprotection – Upregulation of the reparative & restorative responses to oxygen deprivation even under normoxic conditions
  • Cardioprotection has been demonstrated in preclinical trials
  • Others

CLINICAL INFORMATION

Pre Clinical Trials

There have been approximately 100 positive translational in-vitro and in-vivo preclinical studies since the 1950’s demonstrating xenon’s safety and efficacy as both an anesthetic and neuroprotective agent.

Anesthesia/Analgesia:  Xenon has been shown to be a potent NMDAR antagonist with comparable efficacy versus other agents and no known toxicity.

Neuroprotection.  Xenon has demonstrated the following properties in preclinical models:

  • Unique glycine-binding and potent NMDAR antagonist effect with no toxicity observed in any studies
  • Upregulation of anti-apoptotic genes
  • Protection against other anesthetic neurotoxicity, hypoxic-ischemia damage (pre- & post-injury)
  • Superiority vs other gases
  • Synergy with hypothermia

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

Clinical Trials

There have been nearly 100 positive clinical studies mostly demonstrating xenon’s safety and efficacy as an anesthetic agent.  More recently, a Phase II superiority study in post-cardiac arrest syndrome (PCAS) patients published in JAMA in March 2016 showed statistically significantly less brain damage which resulted in directionally positive survival outcomes between a xenon plus targeted temperature management (TTM) versus a TTM-alone group when administered in the critical care setting for 24 hours.

Less Brain Damage:  MRI neuroimaging, which visualized location, orientation, & anisotropy (diffusion differences) of the brain’s white matter tracts, revealed the following:

  • 41.7% less damage in white matter tracts in the brain, P=0.006
  • Less brain damage in areas associated with important cognitive functions, such as attention, memory, language, emotions, auditory, visual and executive processing, and motor functions of the body
  • Treatment effect size of xenon was more than 50% of the difference in the measure observed between survivors and those who died

This MRI biomarker exhibited the best independent predictive value for mortality during the 6-month follow-up period.

Improved Survival:  The Phase II Study (N=110) was not statistically powered to show survival. However, a directionally positive improvement in survival was observed, P = 0.053.

Post analysis of a sub-patient population with return of spontaneous circulation (ROSC) within 30 minutes, which accounted for ~90% of all patients in the Study, revealed a statistically significant relative reduction of ~40% in the rate of mortality. These findings will serve as the basis for the patient inclusion criteria in the Phase III Study.

No Toxicity Observed:  xenon does not accumulate as it is eliminated by exhalation, and is therefore not metabolized.