Stroke treatment and prevention

Longjun ZHU

Longjun.zhu@gmail.com 2012/10/29

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Introduction Treatment & prevention perspective

Outlines

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Introduction

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Road traffic accidents

Diabetes mellitus

Trachea, bronchus, lung cancers

Tuberculosis

HIV/AIDS

Diarrhoeal diseases

Chronic obstructive pulmonary disease

Lower respiratory infections

Stroke & other cerebrovascular disease

Ischaemic heart disease 12.8%10.8%

6.1%5.8%

4.3%3.1%

2.2%2.4%2.4%

2.1%

Top 10 causes of death worldwide (2008)

http://www.who.int/mediacentre/factsheets/fs310/en/index.html

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>80 %

≈20 %

cerebral ischemia

cerebral hemorrhage

Cerebrovascular disease

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What’s stroke?

A stroke is caused by the interruption of the blood supply to the brain, usually because a blood vessel bursts or is blocked by a clot.

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Stroke will lead to permanent cerebral injury

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transient ischemic attack

(TIA , mini stroke )

Sudden severe and unusual headache

Sudden numbness of arms and legs

Classification of Stroke

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Clot forms in body and breaks off, blocking the brain's blood vessels

Embolic Stroke

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Obstruction of a blood vessel by a blood clot forming locally

Thrombotic Stroke

13Thrombus vs embolus difference

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Hemorrhagic stroke

occurs when a blood vessel ruptures and bleeds into the brain

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16Main arterial blood supply to the brain.

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Modifiable Risk Factors

Other Factors:

Poor dietMetabolic syndromePhysical inactivity

AlcoholismDrug use

……

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Treatment and Prevention

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Signs of Stroke

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Massachusetts Department of Public Health

Stroke Heroes Act F.A.S.T

Heart Disease and Stroke Prevention and Control Program @

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CT scans

MRI scans

Doppler ultrasound

Arteriography

Diagnosis

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TherapiesAntithrombotic

antiplatelet agents Anticoagulant

Neuroprotective Free Radical Scavengers Minocycline Growth Factors

Surgery Carotid endarterectomy Carotid stenting craniotomy

22Segers K, Dahlbäck B, Nicolaes GAThromb Haemost:2007 Sep;98(3):530-42

Mechanism of blood coagulation cascade

Antithrombotic

Tenase complex

23Jonathan Cohen Nature 420, 885-891(19 December 2002) doi:10.1038/nature01326

Homeostatic balance between procoagulant and anticoagulant mechanisms

Antithrombotic

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Mechanism of action of main antiplatelet agents.ADP adenosine diphosphate, cAMP cyclic adenosine monophosphate, COX cyclooxygenase, TXA2 thromboxane A2

http://what-when-how.com/myeloproliferative-neoplasms/primary-and-secondary-antithrombotic-prophylaxis-specific-issues-of-treatment-in-pv-and-et-myeloproliferative-neoplasms-part-1/

Antithrombotic

AbciximabTirofiban Eptifibatide

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standard treatment :Aspirin + extended-release DipyridamoleClopidogrel:When aspirin allergy or concurrent symptomatic coronary artery disease

Antiplatelet agents

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BRILINTA US (2011/06/20)

Ticagrelor

Brilique & Possia in the EU (2010/12/03)

The 1st reversible P2Y12 ADP receptor antagonist

ADP Ticagrelor

Better than Clopidogrel

N Engl J Med 2009; 361:1045-1057September 10, 2009DOI: 10.1056/NEJMoa0904327Core Evid. 2011; 6: 31–42. Published online 2011 March 17. doi: 10.2147/CE.S9510

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VorapaxarPrasugrel

Elinogrel

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Anticoagulants such as warfarin(over 50 years) one of the most biologically effective

Anticoagulation drugs

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30Source: Brunton LL, Chabner BA, Knollmann BC: Goodman & Gilman's The Pharmacological Basis of Therapeutics,12th Edition www.accessmedicine.com

Anticoagulant

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The Good NewsDabigatranan alternative to warfarin

Rivaroxaban Apixaban

32The Coagulation Cascade

Warfarin

Rivaroxaban Apixaban

Dabigatran

The Bad News

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• Free Radical ScavengersEdaravone NXY-059

Antibiotics Minocycline

Growth FactorsEpoetin Beta,Trafermin, Filgrastim

neuroprotective

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N

N

OFor the treatment of acute brain ischemia and subsequent cerebral infarction.

Edaravone

•1st free radical scavenger for stroke•Exerts antioxidant effects•Inhibiting radical-dependent and -independent lipid peroxidation•Marketed solely in Japan

• Free Radical Scavengers

Recent Pat Cardiovasc Drug Discov. 2006 Jan;1(1):85-93.BMC Neuroscience 2008, 9:75 doi:10.1186/1471-2202-9-75

BIOMEDICAL REPORTS 1: 7-12, 2013 DOI: 10.3892/br.2012.7METABOLIC BRAIN DISEASE Volume 23, Number 3 (2008), 335-349, DOI: 10.1007/s11011-008-9096-3

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S

SNO

O

O O

O

O

O

Na

Na

NXY-059 (CeroviveR)

•Nitroxide spin trap• Stable free radicals that react with O2

-.

•Marginally positive clinical trial (SAINT I)Failed

• Free Radical Scavengers

http://www.nitrone.com/ http://www.centpharm.com/Stroke. 2006 Dec;37(12):2970-8. Epub 2006 Oct 26.

N Engl J Med 2006; 354:588-600February 9, 2006DOI: 10.1056/NEJMoa052980N Engl J Med 2007; 357:562-571August 9, 2007DOI: 10.1056/NEJMoa070240

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Why did NXY-059 fail???

• Physiochemical shortcomings polar, nonlipophilic nature, poor blood–brain barrier penetrability, nonphysiological oxidation potential, and low potency (Ginsburg, Stroke 2007)

• Lack of biomarker assessing oxidative stress

• Heterogeneity in individual responses to drug treatment

• Stroke is a formidable disorder only one approved therapy to date

Ann Pharmacother March 200640:461-471The Journal of Experimental Biology 207, 3221-3231

37Lampl Y, Boaz M, Gilad R et al. (2007): Neurology 69 (14): 1404–10

Minocycline

Exert inhibition of microglial activity, glutamate toxicity and caspase 1-dependent apoptosis produced by ischemic insults.

acne vulgaris

• Antibiotics

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Growth Factors

Epoetin Beta Basic fibroblast growth factor (bFGF) Filgrastim

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A. carotid angioplasty remove stenosis (atherosclerotic narrowing) of the carotid artery.

Surgery

B. Carotid stentinglarge metal coil (stent) is placed in the carotid artery much like a stent is placed in a coronary artery.

C. craniotomy a type of surgery to remove blood clots or repair bleeding in the brain.

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Prevention of StrokeAntihypertensive Drugs

Valsartan, Losartan, Eprosartan and Telmisartan , Perindopril

Lipid - Lowering Drugs Atorvastatin,Simvastatin,Pravastatin,Rosuvastatin,

Eicosapentaenoic Acid

Hypoglycemic DrugsPioglitazone

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Novel therapies stem-cell therapy repetitive transcranial magnetic stimulation transcranial direct-current stimulation motor imagery virtual reality dopamine agonists Antidepressants novel robotic therapies

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perspective

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Advancement of anti-platelet therapy may be achieved either by dose adjustment of the drug based on functional testing by changing drug combination or by the introduction of more potent and safer drugs.

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Thank you!

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Thank You!