PowerPoint Presentation

Suspended animation: science fiction or plausible therapy?

Mervyn SingerBloomsbury Institute of Intensive Care MedicineUniversity College London, UK

Declaration of interest

Alex Dyson

Therapeutic hypothermia

reduces metabolic ratereduces ROS production .. .. and thus minimizes reperfusion injury

Oh, yes, it works!Oh, no, it doesn't!

TemperatureSurvival

haemorrhagic shock in ratsMAP 40 mmHg for 90 .. then resuscnAfter 15 shock randomized to:normothermia (38C)brief hypothermia (34C) for 15-90 during shock + 30 after reperfusionprolonged hypothermia (as brief, then 35C from 30 to 12h)

Give me a faster alternative!

Maybe we can?

?? hibernation induction trigger (HIT) - 88kDa glycoproteinsynthetic delta opioid peptide, DADLE5-AMP3-iodothyronamine (TIAM)hydrogen sulphide

alsoadenose A1 receptor agonists2-deoxyglucosemethyl palmoxiratemercaptoacetateneuropeptide YPharmacological triggers of torpor

natural daily torpor in micetorpor induced by lowering core temperature to 16C and food deprivation in micetorpor induced by injecting 5-AMP i.p. into mice

Could the answer be found here?

Or even here?

H2S hibernates mice but ...

Our experience with H2S (i.v. NaHS) in rats

Comparing H2S with hypothermia

MGC-0109

oral copper chelatorslow-release intracellular sulphide donor (c/f NaHS which is released intravascularly)

Reduction in whole body VO2 in healthy awake rats(i) short-term dose response curve

placebo MGC-0109

% inhibitionfrom baselineBolus dose (mg/kg)2 5 10 2050

25

0

-25

placeboMGC-0109Reduction in whole body VO2 in healthy awake rats(ii) 24-hour infusion

Drug given on resuscitation, 90 minutes after 50% haemorrhageMGC-0109 in whole-body haemorrhage-reperfusion injury

placeboMLS-001

Drug given on resuscitation, 90 minutes after 50% haemorrhageMGC-0109 in whole-body haemorrhage-reperfusion injury

Core temperatureHeart rate

Protein carbonyls (2h)IL-6 (2h)

placeboMGS-0109

Time post-resuscitation (h)2h post-resuscitation

Myocardial ischaemia-reperfusion injuryLong-term myocardial damage:Ischaemia/infarction from coronary artery occlusionReperfusion injury from PCI

TTMcontrol

%infarctarea at risk

MGC-0109

Resuscitation/treatment of:Acute myocardial infarction + 1 angioplastyCardiac arrest (c/f therapeutic hypothermia)Stroke + thrombolysis/angioplastyAcute trauma ..

Prevention of organ injury:Cardiac bypass surgery Aortic cross clampingTransplantation ..Potential utility ...

Write lots of grantsFind a drug company to fund trialsFind a billionaire

Potential utility -> practical reality

sulphide inhibits mitochondrial respiration and metabolismother useful effects, e.g. anti-inflammatorypotential utility for use in ischaemia-reperfusion injury stateshuman volunteer trials to start 2016 - watch this space!

Conclusion