stroke treatment and perspective
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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!