2006 Advanced Emergency & Acute Care Medicine and Technology Conference

1. ED Ischemic Stroke Patient Neuroprotection: What neuroprotection strategies do we utilize and what might be the role of NXY-059?

2. 2006 Advanced Emergency & Acute Care Medicine and Technology Conference

3. Emergency Medicine AssociatesAtlantic City, NJSeptember 26-27, 2006

4. Edward P. Sloan, MD, MPH FACEP ProfessorDepartment of Emergency MedicineUniversity of Illinois College of MedicineChicago, IL

5. Attending PhysicianEmergency MedicineUniversity of Illinois HospitalOur Lady of the Resurrection HospitalChicago, IL

6. Disclosures • NovoNordisk, King Pharmaceuticals, UCB Pharma Advisory Boards • Eisai Speakers’ Bureau • ACEP Clinical Policies Committee • ACEP Scientific Review Committee • Executive Board, Foundation for Education and Research in Neurologic Emergencies

7. Global Objectives • Maximize patient outcome • Utilize health care resources well • Optimize evidence-based medicine • Enhance ED practice

8. Sessions Objectives • State key questions and concepts • Why perform neuroprotection? • What global neuroprotections? • What specific therapies? • What lies ahead?

9. Case Presentation… 64 year old presents to ED Trouble using L hand and speech Symptoms for last 90 minutes No headache or trauma History of TIA x 1, similar symptoms Hx DM, smoker No recent illness

10. ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size Aggressively Rx ischemic penumbra ED MD is the best neuroprotectant Specific neuroprotectants tested SAINT-I clinical trial showed benefit Specific questions to be addressed

11. ED Neuroprotection: Key Concepts Outcome related to infarct volume

12. Stroke Volume and Outcome Vessel occlusion Infarct core Ischemic penumbra How large is the core in the ED? What is the penumbra conversion? Do ED therapies limit infarct growth?

13. ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size

14. Limiting Stroke Volume Enhance perfusion Treat hypoxia, hypotension Limit ischemic cascade effects Prevent complications Compare the results with a conventional training protocol. Most people do at least two exercises per muscle group, perform three sets and perhaps 12 or 15 reps per set. Allowing just five seconds per rep, that makes for at least 36 minutes of exercise per workout. This is usually done three times per week. So in six weeks, a conventional program would involve 648 minutes of exercise. That's 42 times more than the subjects in our study. Are your results in the last six weeks 42 times better than theirs? I doubt it. Remember, these golfers were exercising in a way that did not involve stretching or moving the weight over a full range of motion. So how did this affect a full range of motion activity like a golf drive? Every one of them showed an improvement. The increase in drive distance varied from 5 to 31 yards. Keep in mind that these subjects had been golfing for up to 40 years and had handicaps as low as eleven. So getting any improvement in golfers who already play at this level is impressive. Getting it with 14 minutes of exercise spread over six weeks is truly revolutionary. The fact is every sport -- even a finesse sport like golf -- is improved by an increase in strength. Muscles are responsible for all movement in the body and stronger muscles deliver more power to every aspect of movement, irrespective of its range of motion. Since this study, I've gone on to improve this method of training. Further research showed that static hold times could be reduced to even less than what the golfers used. Workouts can be spaced further apart as a trainee gets stronger. I work with advanced trainees who train once every six weeks, yet they gain strength on every exercise each time they work out. The weights they hoist are enormous. I believe the time is coming when most people will have a better understanding of the role of proper, efficient strength training methods and frequency. For the guy who wants maximum results with minimum time invested, an ultra-brief but ultra-intense workout will be performed about as often as he gets a haircut. Anything more is just lifting weights as a busy work hobby. Train smart!

15. ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size Aggressively Rx ischemic penumbra

16. Aggressively Rx Ischemic Penumbra Maximize cerebral perfusion Provide optimal substrates, O2 Avoid cell death Maintain intact blood brain barrier

17. Cerebral Perfusion CPP = MAP - ICP Cerebral perfusion pressure Mean arterial pressure Intracranial pressure

18. Cerebral Perfusion CPP = MAP - ICP If MAP = 110 mmHg, ICP 10 mmHg CPP then equals 100 mmHg Cerebral blood flow auto-regulation CPP maintained over range of MAPs Pathological ICP elevations limited

19. Mean Arterial Pressure 120 / 75 MAP = 90 mmHg 210 / 120 MAP = 150 mmHg 180 / 110 MAP = 97 mmHg How much MAP therapy is OK? What agents provide best Rx? How to avoid watershed infarct?

20. Watershed Infarct wa·ter·shed (wô t r-sh d) n. 1. A ridge of high land dividing two areas that are drained by different river systems. Also called water parting. 2. The region draining into a river, river system, or other body of water. 3. A critical point that marks a division or a change of course; a turning point:

21. ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size Aggressively Rx ischemic penumbra ED MD is the best neuroprotectant

22. ED MD: Best Neuroprotectant

23. ED MD: Best Neuroprotectant Available 24/7

24. ED MD: Best Neuroprotectant Available 24/7 Effectively able to diagnose infarct

25. ED MD: Best Neuroprotectant Available 24/7 Effectively able to diagnose infarct Systems expert; able to make things happen quickly

26. ED MD: Best Neuroprotectant Available 24/7 Effectively able to diagnose infarct Systems expert; able to make things happen quickly Focus on acute interventions

27. ED MD: Best Neuroprotectant Available 24/7 Effectively able to diagnose infarct Systems expert; able to make things happen quickly Focus on acute interventions Know our limitations

28. ED MD: Best Neuroprotectant Available 24/7 Effectively able to diagnose infarct Systems expert; able to make things happen quickly Focus on acute interventions Know our limitations We can be trained

29. ED MD Neuroprotection Manage the airway

30. ED MD Neuroprotection Manage the airway ETI, rapid sequence induction

31. ED MD Neuroprotection Manage the airway ETI, rapid sequence induction Manage hypotension

32. ED MD Neuroprotection Manage the airway ETI, rapid sequence induction Manage hypotension Manage hypertension

33. ED MD Neuroprotection Manage the airway ETI, rapid sequence induction Manage hypotension Manage hypertension Treat metabolic abnormalities

34. ED MD Neuroprotection Manage the airway ETI, rapid sequence induction Manage hypotension Manage hypertension Treat metabolic abnormalities Diagnose and lower elevated ICP

35. ED MD Neuroprotection Manage the airway ETI, rapid sequence induction Manage hypotension Manage hypertension Treat metabolic abnormalities Diagnose and lower elevated ICP Prevent and treat seizures

36. ED MD Neuroprotection Manage the airway ETI, rapid sequence induction Manage hypotension Manage hypertension Treat metabolic abnormalities Diagnose and lower elevated ICP Prevent and treat seizures We first do no harm

37. ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size Aggressively Rx ischemic penumbra ED MD is the best neuroprotectant Specific neuroprotectants tested

38. Stroke Pathophysiology, Neuroprotectants

39. Stroke Pathophysiology, Neuroprotectants Lubeluzole Fosphenytoin Sipatrigine Riluzole Lamotrigine Lifarizine Maxipost

40. Stroke Pathophysiology, Neuroprotectants

41. Stroke Pathophysiology, Neuroprotectants Aptiganel Selfotel GV-150526 CP-101606 Eliprodil ACPC ACEA 1021 Dizocilpine Dextromethorphan NBQX Magnesium

42. Stroke Pathophysiology, Neuroprotectants

43. Stroke Pathophysiology, Neuroprotectants GM1 Piracetam Tirilizad PEG SOD PNA Enlimomab Citicoline CX295 Ceresine

44. Stroke Pathophysiology:Free Radical Formation

45. Stroke Pathophysiology:Free Radical Formation Tirilazad Citicoline Ebselen NXY-059

46. Neuroprotection 1955-2000 Trials of Neuroprotection Agents in Stroke:1955-2000 This year, first positive primary endpoint trial Kidwell CS et al. Stroke 32(6):1349-59.

47. Why have neuroprotection agents failed in human trials? • Wrong theoretical concept • Treatment initiated too late • Stroke heterogeneity • Wrong drug action • Doses too low • Trials underpowered • Wrong outcome measures • Insensitive statistical techniques

48. ED Neuroprotection: Key Concepts Outcome related to infarct volume Need to limit infarct size Aggressively Rx ischemic penumbra ED MD is the best neuroprotectant Specific neuroprotectants tested SAINT-I clinical trial showed benefit

49. NXY-059 (Cerovive) 2006;354(6):588-600.

50. NXY – 059 Characteristics • NXY-059 (Cerovive) is an intravenous, nitrone-based, free radical trapping agent • Preclinical trials positive in rats/primates • Effective after 4 hours of ischemia • Significant dose response