Suspended Animation by Mervyn Singer

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Is Suspended Animation only in the realms of science fiction, or is this a realsitic treatment option? Mervyn Singer questions if we can prevent secondary reperfusion injury following cerbral ischaemia.

Salud y medicina

Suspended animation:
science fiction or plausible therapy?
Mervyn Singer
Bloomsbury Institute of
Intensive Care Medicine
University College London, UK

Therapeutic hypothermia
 reduces metabolic rate
 reduces ROS production ..
.. and thus minimizes reperfusion injury

haemorrhagic shock in rats
MAP 40 mmHg for 90’ .. then resusc’n
After 15’ shock randomized to:
 normothermia (38°C)
 brief hypothermia (34°C) for 15-90’
during shock + 30’ after reperfusion
 prolonged hypothermia (as brief, then
35°C from 30’ to 12h)

 ?? hibernation induction trigger (HIT) - 88kDa glycoprotein
 synthetic delta opioid peptide, DADLE
 5-AMP
 3-iodothyronamine (TIAM)
 hydrogen sulphide
also
 adenose A1 receptor agonists
 2-deoxyglucose
 methyl palmoxirate
 mercaptoacetate
 neuropeptide Y
Pharmacological triggers of torpor

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

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

MGC-0109
oral copper chelator
slow-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
% inhibition
from baseline
Bolus dose (mg/kg)
2 5 10 20
50
25
0
-25

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

Drug given on resuscitation, 90 minutes after 50% haemorrhage
MGC-0109 in whole-body haemorrhage-reperfusion injury
placebo
MLS-001

Drug given on resuscitation, 90 minutes after 50% haemorrhage
MGC-0109 in whole-body haemorrhage-reperfusion injury
Core temperature Heart rate Protein carbonyls (2h) IL-6 (2h)
placebo
MGS-0109
Time post-resuscitation (h) 2h post-resuscitation

Myocardial ischaemia-reperfusion injury
Long-term myocardial damage:
Ischaemia/infarction from coronary artery occlusion
Reperfusion injury from PCI
0
10
20
30
40
TTM control
%infarct
area at risk
MGC-0109

Resuscitation/treatment of:
Acute myocardial infarction + 1° angioplasty
Cardiac arrest (c/f therapeutic hypothermia)
Stroke + thrombolysis/angioplasty
Acute trauma ..
Prevention of organ injury:
Cardiac bypass surgery
Aortic cross clamping
Transplantation ..
Potential utility ...

Write lots of grants
Find a drug company to fund trials
Find a billionaire
Potential utility -> practical reality

 sulphide inhibits mitochondrial respiration and metabolism
 other useful effects, e.g. anti-inflammatory
 potential utility for use in ischaemia-reperfusion injury states
 human volunteer trials to start 2016 - watch this space!
Conclusion

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Suspended Animation by Mervyn Singer

1. Suspended animation: science fiction or plausible therapy? Mervyn Singer Bloomsbury Institute of Intensive Care Medicine University College London, UK

2. Declaration of interest

3. Alex Dyson

5. Therapeutic hypothermia  reduces metabolic rate  reduces ROS production .. .. and thus minimizes reperfusion injury

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

10. Temperature Survival

11. haemorrhagic shock in rats MAP 40 mmHg for 90’ .. then resusc’n After 15’ shock randomized to:  normothermia (38°C)  brief hypothermia (34°C) for 15-90’ during shock + 30’ after reperfusion  prolonged hypothermia (as brief, then 35°C from 30’ to 12h)

12. Give me a faster alternative!

13.

14. Maybe we can…?

15.

16.  ?? hibernation induction trigger (HIT) - 88kDa glycoprotein  synthetic delta opioid peptide, DADLE  5-AMP  3-iodothyronamine (TIAM)  hydrogen sulphide also  adenose A1 receptor agonists  2-deoxyglucose  methyl palmoxirate  mercaptoacetate  neuropeptide Y Pharmacological triggers of torpor

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

18. Could the answer be found here?

19. Or even here?

20.

21.

22.

23. H2S hibernates mice but ...

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

25. Comparing H2S with hypothermia

26. MGC-0109 oral copper chelator slow-release intracellular sulphide donor (c/f NaHS which is released intravascularly)

27. Reduction in whole body VO2 in healthy awake rats (i) short-term dose response curve placebo MGC-0109 % inhibition from baseline Bolus dose (mg/kg) 2 5 10 20 50 25 0 -25

28. placebo MGC-0109 Reduction in whole body VO2 in healthy awake rats (ii) 24-hour infusion

29. Drug given on resuscitation, 90 minutes after 50% haemorrhage MGC-0109 in whole-body haemorrhage-reperfusion injury placebo MLS-001

30. Drug given on resuscitation, 90 minutes after 50% haemorrhage MGC-0109 in whole-body haemorrhage-reperfusion injury Core temperature Heart rate Protein carbonyls (2h) IL-6 (2h) placebo MGS-0109 Time post-resuscitation (h) 2h post-resuscitation

31. Myocardial ischaemia-reperfusion injury Long-term myocardial damage: Ischaemia/infarction from coronary artery occlusion Reperfusion injury from PCI 0 10 20 30 40 TTM control %infarct area at risk MGC-0109

32. Resuscitation/treatment of: Acute myocardial infarction + 1° angioplasty Cardiac arrest (c/f therapeutic hypothermia) Stroke + thrombolysis/angioplasty Acute trauma .. Prevention of organ injury: Cardiac bypass surgery Aortic cross clamping Transplantation .. Potential utility ...

33. Write lots of grants Find a drug company to fund trials Find a billionaire Potential utility -> practical reality

34.  sulphide inhibits mitochondrial respiration and metabolism  other useful effects, e.g. anti-inflammatory  potential utility for use in ischaemia-reperfusion injury states  human volunteer trials to start 2016 - watch this space! Conclusion

Suspended Animation by Mervyn Singer

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