STROKE

Prepared by: Cheok Ken Yew Chan Sook Yeen Kaveeta Pergas Lai Shu Mei Mabel Cheong Sook Ling

STROKE
global

epidemic neurological deficit disease third leading cause of death in Malaysia and worldwide 52000 Malaysians suffered strokes annually six new cases every hour caused by insufficient blood supply to the brain or hemorrhage into brain tissue 2 main types: - ischemic stroke - hemorrhagic stroke

paralysis, loss of vision and speech, sudden numbness, and confusion Risk factors: - non-modifiable: age, gender, hereditary - modifiable: hypertension, heart disease, smoking, obesity, hyperlipidemia Complications: extracranial bleeding, depression, physical and cognitive impairment, coma, death Pharmacological intervention: thrombolytic agent and anti-platelet drug Preventive measures are taken to minimize stroke frequency, mortality and morbidity.
Symptoms:

F.A.S.T. CAMPAIGN

Facial weakness check face if mouth drooped? Arm weakness can they lift both arms? Speech difficulty slurred speech? Do they understand you? Time is critical Recognizing any of these signs can be the difference between death or severe disability and making a good recovery

algorithm for treatment options in stroke

ACUTE TREATMENT OF ISCHEMIC STROKE

In general, the ONLY two pharmacologic agents recommended with a *grade A recommendations are IV t-PA within 3 hours of onset and aspi i within 48 hours of onset Reperfusi of ischemic brai with the concept of ischemic penumbra existence, adjacent dysfunctional tissue might be salved albeit core infarct tissue may not be salvageable in restoring circulation and metabolism

* Grade A recommendations based on at least one meta analysis, systemic review, or RCT, or evidence rated as good and directy applicable to the target population

ACUTE TREATMENT OF ISCHEMIC STROKE

Treatment Recommendations

rt-Pa (recombinant tissuetype plasminogen activator) e.g. alteplase

In selected patients presenting within 3 hours: IV rt-pa (0.9mg/kg, maximum 90mg) with 10% given as a bolus followed by an infusion over one hour Start aspirin within 48 hours of stroke onset. Use aspiring within 24 hours of rt-Pa is not recommended

Aspirin

Acute Treatment of Ischemic Stroke

Treatment

Recommendations

Anticoagulants

The use of heparins (unfractionated heparin, low molecular weight heparin or heparinoids) is not routinely recommended as it does not reduce the mortality in patients with acute ischemic stroke A large number o clinical trials testing a variety of neuroprotective agents have been completed but produced negative results thus far. To date, no agents of this class can be recommended for treatment at this time

Neuroprotective agents

SECONDARY PREVENTION
Antiplatlet therapy -Aspirin, Clopidogrel, Ticlopidine, Dipyridamole
  

Anticoagulants Warfarin

Anti-hypertensive treatment -ACEIs , ARBs

 Lipid

lowering agents -Statins

 Better

glycaemic control in diabetes and smoking cessation

TREATMENT Antiplatelets: SINGLE AGENTS: Aspirin Alternatives: Clopidogrel Ticlopidine

RECOMMENDATION

-75mg to 325mg daily.

-75 mg daily. -250mg twice a day.

DOUBLE THERAPY: Addition of Clopidogrel to Aspirin -In selected high risk patients only when benefit outweighs risk

Anti-Hypertensives

-ACE-inhibitor -ARB-based therapy may benefit selected high risk populations

TREATMENT Lipid lowering

RECOMMENDATION Lipid reduction should be considered in all subjects with previous ischaemic strokes. All diabetic patients with a previous stroke should improve glycaemic control. All smokers should stop smoking

Diabetic control

Cigarette smoking

MOA OF ASPIRIN

Aspirin irreversibly binds to COX-1 and COX-2.

Inhibition of prostaglandin and thromboxane A2 synthesis.

COX-1 inhibition mediates inhibition of thromboxane A2 synthesis within the platelet.

Inhibit platelets activity.

PHARMACOLOGIC PROFILE OF ASPIRIN

Rapidly

absorbed from the stomach and small intestine.

Then hydrolyzed to salicylic acid by esterases.

Average

half-life in plasma is 15 to 20 minutes. The

oral bioavailability is 40 to 50% at therapeutic doses.

Excreted

in the urine as salicylic acid and other

metabolites.

ASPIRIN

Prevent serious vascular events in stroke survivor, Reduce stroke recurrence Improve survival rate Cost effective

ASPIRIN DRAWBACKS

Bleeding

Not for asthma

Renal impairment Pregnancy Class C

CI for children <16 yrs

Gastrointestinal problems

CONCLUSION
Stroke

is a disabling and fatal disease.

Prevent stroke by knowing symptoms.

Despite

certain drawbacks of Aspirin it is still a good medication for stroke.

REFERENCES

Antonio Di Carlo (2009) Human and economic burden of stroke. Oxford Journals. 38(1): 4-5 Stroke Prevention (n.d.) [online]. Available: http://www.nasam.org/english/preventionwhat_is_a_stroke.php [Accessed 24 April 2011]. Killer stroke: Six Malaysians hit every hour (n.d.) [online]. Available: http://thestar.com.my/news/story.asp?file=/2007/4/24/nation/17524877&sec=nation [Accessed 24 April 2011]. Management of stroke (2006). Clinical practice guidelines (Malaysia).

Kenda S. Fuller. (2009) C.C Goodman Pathology. Implication for the Physical Therapist 3rd Ed. Saunders. Chap. 32 Stroke; pp 1461-1463 Amann, R. and Peskar, B.A. (2002) Anti-inflammatory effects of aspirin and sodium salicylate. Eur J Pharmacol. 447: 1-9. Aspirin. Drug Facts and Comparisons. Efacts [online]. 2007. Available: Wolters Kluwer Health, Inc.

Patrono, C. et al (2005) Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med. 353: 2373-83.

Schrder H. and Schrr K. (1992) Clinical pharmacology of acetylsalicylic acid. Z Kardiol. 81(4): 171-5.

Antiplatelet Trialists Collaboration (1994) Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 308: 81106.

RIVAROXABAN BY CHEOK

Rivaroxaban
Xarelto (Brand name)

Available in 10 mg oral dose. Taken once daily. Antiplatelets &(Thrombolytics) agent

Indications
Prevent venous

thromboembolism (VTE) in hip and knee surgery.

Prevent strokes due to atrial fibrillation.

MOA
Inhibition of Factor Xa.

Prothrombin cannot convert to thrombin.

No fibrin clot formed and activation of platelets.

Pharmacokinetics
Bio-availabiliy 80-100 % (Cmax) 2-4 hrs after intake Taken with or without food
2/ 3

undergo metabolism

Excreted by renal and fecal route.

Adverse reactions
Hepatic impairment

Occult bleeding in organ and tissues Post-operative anemia Wound healing complications

Contraindications
Hepatic and renal

impairment. Children <18 yr. Pregnancy & lactation. High bleeding risk. Lactose intolerance.

Usage for stroke

Study still in Phase 3 trials.

Not approved by FDA

Stroke occurrence lesser than

warfarin.

Aspirin Inhibit thromboxane A2

Bio-availability 50-80%

Rivaroxaban
Inhibit Factor Xa Bio-availability 80-100%

Proven to be effective for stroke.

On going clinical trials.

Aspirin
Gastric irritation & kidney impairment.

Rivaroxaban
Hepatic impairment.

RM 30 per month

RM 618 per month

Contraindication : Asthma

Contraindication : Lactose intolerance

Rivaroxaban vs Warfarin
Outcome
Vascular death, stroke, embolism Hemorrhagic stroke Rivaroxaban 3.11 Warfarin 3.63

0.26

0.44

Ischemic stroke

1.34

1.42

Rivaroxaban vs Warfarin
Outcome Major bleeding Rivaroxaban 3.60 Warfarin 3.45

INR monitoring

NO

YES

Discussion
Aspirin is the better drug Compared to warfarin, has more benefit Warfarin is more cost-effective. Rivaroxaban has higher bleeding risk Long-term adverse effects unknown

Conclusion
Rivaroxaban shows potential to be an effective medication for stroke. Needs many years to establish reputation as a safe and good drug. Anyway Kuala Lumpur wasnt built in a day.

Reference

ROCKET AF Study Investigators. (2010). Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF s. PubMed U.S. National Library of Medicine National Institutes of Health. 159 (3), p340-347. http://www.mims.com/Malaysia/drug/info/Xarelto/Xarelto%20film-coated%20tab?type=full Patrono, C. et al. (1994). Drug Therapy: Aspirin As Antiplatelet Drug. The New England Journal of Medicine. 330 (8), p1287-1294. Harold P.Adams, JR. (2007). Principles of Cerebrovascular Disease. United States: Mc Graw Hill. p1 & p385. The EINSTEIN Investigators. (2010). Oral Rivaroxaban for Symptomatic Venous Thromboembolism. The New England Journal of Medicine. 363(26), p 2499 2510.

Presented by: Mabel Cheong Sook Ling 01BP-200804-00013

 Ticagrelor (BriliqueTM)

- a new drug that has just received approval from the European Commission and is waiting for FDA approval. It is approved to be co-administered with aspirin in the prevention of thrombotic events in patients with acute coronary syndromes. It is a member of the chemical class cyclopentyltriazolopyrimidines (CPTP).

 Ticagrelor is

a selective adenosine diphosphate (ADP) receptor antagonist that acts on the P2Y12 ADP-receptor. This prevents platelet activation and aggregation which are mediated by ADP. Ticagrelor reversibly interacts with the platelet P2Y12 ADP-receptor. It does not interact with the ADP binding site itself, but interacts with the receptor to prevent signal transduction.

 Ticagrelor is

orally active but has a relatively low

solubility. At least 56% of the drug is absorbed following oral administration. Ticagrelor is absorbed throughout the small intestine, but absorption reduces further down the gastrointestinal tract. No clinically relevant food effect was observed for this drug. Absolute bioavailability is approximately 36%.

Ticagrelor does not extensively distribute into or bind to tissues. Ticagrelor and its primary active metabolite bind extensively (>99.7%) to plasma proteins. It undergoes extensive metabolism to produce a total of 10 metabolites which are excreted in urine and faeces. It demonstrates a rapid onset of effect, with inhibition of platelet aggregation statistically significant at all times (0.5 hours to maximum response at 8 hours).

Feature Indication

Aspirin MI prophylaxis Mild to moderate pain and fever Acute and chronic musculoskeletal conditions and rheumatic disorders

Ticagrelor Co-administered with aspirin in the prevention of thrombotic events in patients with acute coronary syndromes

Mechanism of action Irreversibly binds to COX1 and COX-2 enzymes, inhibiting thromboxane A2 synthesis in platelets

Selective ADP receptor antagonist that acts on the P2Y12 ADP-receptor, preventing platelet activation and aggregation mediated by ADP 1. % death reduction

Efficacy in stroke prevention

22% risk reduction Reduces recurrence rate and improving survival.

Feature Absorption

Aspirin Absorbed from stomach and small intestine Absorption affected by food

Ticagrelor Absorbed throughout the small intestine but absorption reduces further down the GI tract Absorption not affected by food

Bioavailability Metabolism

40 - 50 Primary metabolite: salicylic acid (hydrolysis by esterases in gastrointestinal mucosa and plasma) Urine

36 Undergo extensive metabolism to produce a total of 10 metabolites

xcretion

Urine and faeces

Feature Side effect

Aspirin Gastrointestinal, intracerebral and other bleedings, bronchospasm Tablet, caplet and coated tablet

Ticagrelor Bleeding events, dyspnea, headache, epistaxis Film-coated tablet

Dosage form

When ticagrelor is compared to clopidogrel, ticagrelor does not require metabolic activation and demonstrates greater platelet inhibition, a faster offset of action and comparable bleeding risk. The pivotal PLATO (The Study of Platelet Inhibition and Patient Outcomes) trial in patients with an acute coronary syndrome showed that ticagrelor improved cardiovascular outcomes, including a reduction in myocardial infarctions and vascular events compared to clopidogrel with comparable rates of major bleeds.

Efficacy of ticagrelor demonstrated a clear beneficial treatment effect for the prevention of cardiovascular death and myocardial infarction. does not provide significant treatment effect on the prevention of stroke death.
It Ticagrelor

 The

most important safety indicator for anticoagulants and antiplatelets - risk of bleeding: similar level for ticagrelor as with clopidogrel (for major and death/lifethreatening bleedings) Specific bleedings or cases are associated with a higher bleeding risk. Adverse events include dyspnea, arrhythmic effect, increased uric acid, higher serum creatinine.

 Ticagrelor is

easy to be taken as it is available as round, biconvex, yellow, film-coated tablet A trial showed that ticagrelor ($3.00 to $4.65 per day) provides an economical gain in qualityadjusted life 12 months (QALY) in comparison with clopidogrel ($0.23 per day). ~Patients treated with ticagrelor and aspirin, compared with clopidogrel plus aspirin for 12 months have been estimated to achieve an additional 0.13 QALYs at a price range of $7,550 per QALY.

 Aspirin

works better for stroke prevention compared to ticagrelor. Nevertheless, ticagrelor has its own advantages when a combination therapy with aspirin is indicated. Therefore, aspirin may be used as single agent therapy, while ticagrelor plus aspirin may be chosen as combination therapy for stroke prevention.

European Medicines Agency (2011) Assessment Report for Brilique. London: EMA.

ealth Economics Substudy of PLATO Shows BRILIQUE to be a Cost Effective Remedy Versus Generic Clopidogrel (2011) [online]. Available: http://www.pharmaceutical-networking.com/healtheconomics-substudy-of-plato-shows-brilique-to-be-a-cost-effectiveremedy-versus-generic-clopidogrel/ [Accessed 8 May 2011].

Nawarskas, J.J. and Clark, S.M. (2011) Ticagrelor: A Novel Reversible Oral Antiplatelet Agent. Cardiology in Review. 19(2): 95-100.

UBM Medica (2011) aspirin Full Prescribing Information, Dosage & Side

http://www.mims.com/USA/drug/info/aspirin/?type=full&mtype=generic#Dosage [Accessed 22 May 2011].

ffects [online]. Available:

Only about seventy years ago was chemistry, like a grain of seed from a ripe fruit, separated from the other physical sciences. With Black, Cavendish and Priestley, its new era began. Medicine, pharmacy, and the useful arts, had prepared the soil upon which this seed was to germinate and to flourish. Justus von Liebig

PRADAXA for stroke management

presented by Caren Chan ID. No: 15719547

Pradaxa is indicated to reduce the risk of stroke and systemic

embolism in patients with non-valvular atrial fibrillation

Dose: 150mg PO twice daily. Therapy should be continued life-

long. Elderly 80 yr 110 mg twice daily

Dosage Form: capsule with light blue opaque cap

imprinted in black with the manufacturer company symbol and a cream-coloured opaque body imprinted in black with R150 (150mg) or R75 (75mg)

Description
y Administration may be taken with or without food but is intended

to swallow whole, do not chew/crush

y Warfarin may have a long history of clinical use with an antidote

available in case of major bleeding, but it has many limitations to its use
y Warfarin has an unpredictable and variable effect, a narrow

therapeutic window requiring frequent INR monitoring, and numerous food and drug interactions, which all contribute to poor compliance
y On the other hand, Pradaxa has fewer drug interactions and routine

monitoring is not required

Description
y However, there is no specific antidote for dabigatran in

case of major bleeding

y Dabigatran is the first oral anticoagulant available

since the approval of warfarin over 50 years ago

y Dabigatran (Pradaxa) was approved in Octorber 2010 y Data from RE-LY (Randomized Evaluation of Long-

term Anticoagualant Therapy) indicate dabigatran 150mg PO twice daily was associated with lower rates of stroke and systemic embolism compared to warfarin

Dabigatran and its active metabolites are competitive, direct thrombin inhibitors which inhibit both free and clot-bound thrombin Dabigatran prevents thrombin-induced platelet and the development of a thrombus by preventing the thrombin-mediated conversion of fibrinogen intro fibrin during the coagulation cascade

Pharmacologic Profile
y After oral absorption, it is metabolized by esterases to its four competitive active acyl glucoronides, active moieties y Dabigatran is eliminated primarily in the urine y Dabigatran half-life is 12-17 hours y Bleeding is the most relevant side effect of Pradaxa; indigestion, upset stomach, or burning, stomach pain y Contraindicated in severe renal imparied patients

(CrCl <30 mL/min); active bleeding; hepatic impairment or liver disease

Pharmacologic Profile
y Neonates, Infants, Children, and Adoloscents: Safety

and efficacy have not been established

y Pregnancy category C. No clinical data on exposed

pregnancies are available. The potential risk for humans is unknown.

y Women of childbearing potential should avoid

pregnancy during treatment with Pradaxa and when pregnant, women should not be treated with Pradaxa unless the expected benefit is greater than the risk

Packing/Price
y Pradaxa 75 mg x 30's (RM393.75) y Pradaxa 110 mg x 30's (RM393.75) y Bottle y Blister y Store at 15C to 30C. After opening the bottle, use Pradaxa within 30 days. y Safely throw away any unused Pradaxa after 30 days. Protect from moisture.

Comparison between aspirin and pradaxa

Properties
Active metabolite Use/Indication Mechanism

Aspirin
Salicylate Platelet COX (potently COX-1) enzymes inhibitor.

Pradaxa
Dabigatran

Prophylaxis stroke management

Dabigatran and its acyl glucoronides compete directly to inhibit thrombin. Preventing thrombus formation thus, absence of thrombin-induced platelet aggregation. No Liver Esterase - catalyzed hydolysis 150mg twice daily 12-17 hours

Anti-inflammatory effects Site of metabolism

Yes

Liver, plasma, erythrocytes, and synovial fluid Metabolic enzymes Carboxyesterases Daily maintenance dose 75mg once daily with food t1/2 (half-life) 15-20 minutes (aspirin) Salicylate: 2-3 hours (low dose salicylate) 15-30 hours (high dose salicylate) Time for peak conc. 60-120 mins (uncoated tablets) (min) *varies with different dosage forms

60 (fasting) 120 (high-fat meal)

Comparison between aspirin and pradaxa

Properties
Bleeding risk Administration Resistance Used for stroke Pediatric use Pregnancy category Dosage form (s) Storage

Aspirin
Moderate With food Yes Yes Yes (D third trimester) Oral tablets ,capsule, gum; Suppositories Room temperature, avoid excessive heat and humidity - Oral (15-25 ) Rectal (2-15 )

Pradaxa
Severe With / Without food. Swallow whole. Do not crush or chew Unknown Yes Unknown (inade uate studies in pregnant women) apsules Unit bottle of 60 capsules - Once opened, product must be used within 30 days Blister package containing 60 capsules (10 x 6 capsule blister cards) *FDA special storage and handling re uirement

Critical appraisal of the new drug

y Besides aspirin s antiplatelet activity, higher dosages of aspirin (1.3 g/day) may decrease vascular plasminogen activator, thereby increase thrombus formation stroke y Aspirin dose of 75 to 325 mg/day were effective in secondary stroke prevention indefinitely y Aspirin is cost saving - it reduces costs at the same time as saving QALYs (quality-adjusted life-years saved) findings of a total cost per stroke prevented was $16 savings if the intracerebral bleeding was 0.3% and $43 if the bleeding rate was 2% y The Warfarin Aspirin Recurrent Stroke Study, warfarin (INR = 1.4 2.8) was not superior to aspirin 325 mg/day in the prevention of recurrent y Thus, most clinicians abandon the practice of using warfarin in all but patients with cardioembolic sources of emboli, mainly atrial fibrillation

Critical appraisal of the new drug

y Dabigatran is a potent, synthetic, reversible, non-peptide thrombin inhibitor y 150mg twice daily y Compared with warfarin, dabigatran etexilate is 10-30 times more expensive y Clinically, warfarin is used to prevent and treat thromboembolic disease with various clinical condition y Dabigatran reduces stroke risk to an even greater extent than warfarin. However, as to replace warfarin to dabigatran in stroke management is still questionable y The INR test is relatively insensitive to the activity of dabigatran and may or may not be elevated with Pradaxa y Among these three drugs, warfarin requires the most aggressive monitoring (in case of bleeding), followed by aspirin then dabigatran

Clinical Comparison Report

Aspirin
Can be used for atrial fibrillation? Can be used for ischemic stroke? Can be used for stroke prophylaxis? Can be used for TIA (transient ischemic attack)? Is contraindicated in or should be used cautiously in stroke?

Warfarin

Dabigatran

No Yes Yes Yes

Yes No Yes No

Yes No Yes No

No

Yes

No

Clinical Comparison Report

Aspirin
Is contraindicated in or should be used cautiously in GI bleeding? Is it contraindicated in or should be used cautiously in bleeding? Packing/Pricing

Warfarin

Dabigatran

Yes

Yes

No

No

Yes

Yes

Aspirin Bayer 0.5 g x 24's (RM10.80)

Apo-Warfarin 1 mg x 100's Apo-Warfarin 2 mg x 100's Apo-Warfarin 5 mg x 100's

Pradaxa 75 mg x 30's (RM393.75) Pradaxa 110 mg x 30's (RM393.75) for elderly 80 years

Conclusion
y Pradaxa may emerge as a new intervention, but its current status of

studies is insufficient for confidence as drug of choice for stroke management reduced ischemic and hemorrhagic strokes relative to warfarin stroke management which is

y RE-LY study reported that Pradaxa 150mg twice daily significantly y My personal view would be for the use of aspirin as prophylaxis
y relatively lower cost of pharmaceutical approaches, y minimized bleeding risk by lowering the optimum dosage, y patient compliance test,

until further studies conducted on Pradaxa, proving confidence as alternative drug of choice y The only attraction Pradaxa bought about is requiring no

aggressive monitoring compare to other anticoagulants

y Hence, appropriate and thorough studies on therapy regime may

reduce stroke morbidity and mortality

References
y International Stroke Trial Collaboration Group. (1997) The International Stroke Trial

(IST): A randomized trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischemic stroke. Lancet:349;1560-1581.

y Clinical Pharmacology.(2011) Elsevier. [online]: http://0-clinicalpharmacology-

ip.com.alpha2.latrobe.edu.au/default.aspx

y Pradaxa Prescribing Information. Drug Infromation Online. Drugs.com.(2010)

[online]: http://www.drugs.com/pro/pradaxa.html

y Eline A. Et al. (2010) New Drug Mechanism. Dabigatran etexilate. BJCP:70:1;14-

15.

y Safety Information. U.S. Food and Drug Administration. (2011) [online]:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMe dicalProducts/ucm249005.htm

THANK YOU
Take care of your body with steadfast fidelity. The soul must see through these eyes alone, and if they are dim, the whole world is clouded.
- Johann Wolfgang Von Goathe (1749-1832)

Drug Research Report

Formulation C (Individual Presentation)

ATryn
By, Kaveeta Pergas BP01-200904-00032 Bachelor of Pharmacy

ATryn
Recombinant form of human antithrombin  Made from the milk of goats that have been genetically modified to produce human antithrombin.[1] Initial FDA Approval: February 2009

Introduction
First ever transgenically produced therapeutic protein and the first recombinant antithrombin. Works by regulating the clotting and inflammatory processes that lead to the formation of blood clots. Indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients.[2] Correlated with a reduced risk of stroke.

Transgenic Goats

AIM: - Restore a normal level of antithrombin activity while the patient is at risk of blood clot formation. [3]  DOSAGE FORM & ROUTE OF ADMINISTRATION: - Powder for reconstitution designed for intravenous administration. - For single dose use only.  DOSE: - Individualized based on the patient s pre-treatment functional antithrombin activity level & body weight . [3] - Requires monitoring
*Store at 2-8C

 CONTRAINDICATIONS: -Hypersensitivity to goat and goat milk proteins. [4]  WARNING & PRECAUTIONS: -Anaphylaxis and severe hypersensitivity reactions are possible. -Coagulation Monitoring Test DRUG INTERACTIONS: -Heparin or other anticoagulants ADVERSE REACTIONS: -Hemorrhage

 USE IN SPECIFIC POPULATIONS -Pregnancy -Nursing mothers

NOTE!!!

Atryn does not contain any preservatives nor is it formulated with human plasma proteins

 MECHANISM OF ACTION - Antithrombin (AT) plays a central role in the regulation of hemostasis. - AT is the principal inhibitor of thrombin and Factor Xa, the serine proteases that play pivotal roles in blood coagulation. - AT neutralizes the activity of thrombin and Factor Xa by forming a complex which is rapidly removed from the circulation. - The ability of antithrombin to inhibit thrombin and Factor Xa can be enhanced by greater than 300 to 1000 fold when AT is bound to heparin.

PHARMACODYNAMICS -Hereditary AT deficiency causes an increased risk of venous thromboembolism (VTE).[5] -During high-risk situations such as surgery or trauma or for pregnant women, during the peripartum period, the risk of development of VTEs as compared to the normal population in these situations is increased by a factor 10 to 50 .[6,7] - In hereditary antithrombin deficient patients ATryn restores (normalizes) plasma AT activity levels during peri-operative and peri-partum periods.

ASPIRIN Anti platlet Cheap Oral (Diluted in water or chewed) Hypersensitivity to salicylates Aspirin works as a blood thinner, helping

ATRYN Antithrombin (Recombinant) Expensive IV Hypersensitive to goat products Atryn works by regulating the clotting

to prevent the further formation of stroke- and inflammatory processes that lead to causing clots. the formation of blood clots.

Produced from drug active ingredients Hemorrhagic stroke. While daily aspirin can help prevent a clot-related stroke, it

Produced from transgenic goats Potential safety issue is the development of an immunological reaction to the

may increase the risk of a bleeding stroke. recombinant protein or any of the potential contaminating proteins.

Critical Appraisal
Convinience: -Treatment with ATryn should only be started by doctors who are experienced. -Require trained staff -Proper handling Safety: -Patients could develop antibodies (proteins produced in response to the medicine) with a risk of an allergic reaction at the time of injection. -Clinical trials are still ongoing

 Effectiveness: -Not beneficial for someone who has a normal level of circulating antithrombin[8]. -May be more effective for dissolving artery blocking clots in the brain during the critical early stages of stroke instead of being used as a prevention from stroke. Cost: -Presumably expensive -The cost of a pack of 10 x 1750 IU vials is 17,850[9]. -75 kg patient, the cost of treatment is approximately 11,000 per day! -Cost for ongoing clinical trials

 Shortcomings: -Animal health and welfare, in particular, are not adequately considered. - Animal ethics- cruelty to goats -Fewer than 10 out of every 100 animals injected with the human gene while still in their mother's womb will be able to produce the altered milk[10]. -Cases where certain "successful" transgenic baby goats develop severe birth defects that scientists don't understand.

ADVANTAGES
Capacity Scale Harvesting

DISADVANTAGES
Time Animal Ethics Lactation

Conclusion
Over the last decade, major advances have been made in the prevention of stroke, but it all falls back on Aspirin. There is no surprise why Aspirin has been given the name Wonder Drug . It is easy to manufacture, cost effective in manufacturing and sales, convenient route of administration, effective dosage, and most importantly it is more suitable to be used in the prevention of stroke.

References
1. Heavey, Susan (6 February 2009). "U.S. approves first drug from DNA-altered
animals". Reuters.Retrieved Feb 7, 2009. 2. Patnaik MM,Moll S.Inherited antithrombin deficiency: A Review. Haemophilia 2008;14:1229-39. 3. Edmunds T, Van Patten SM, Pollock J et al. Transgenically produced human antithrombin: structural and functional comparison to human plasma-derived antithrombin. Blood 1998 June 15;91(12):4561-71. 4. Echelard Y, Meade H, Ziomek C. The first biopharmaceutical from transgenic animals: ATryn. Modern Biopharmaceuticals 2005;995-1016. 5. Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs 2007;67(10):1429-40. 6. Buchanan GS, Rodgers GM, Ware Branch. The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation. Best Pract Res Clin Obstet Gynaecol 2003 June;17(3):397-411. 7. Walker ID, Greaves M, Preston FE. Investigation and management of heritable thrombophilia. Br J Haematol 2001;114:512-28. 8. Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs 2007;67(10):1429-40. 9. Echelard Y, Meade H, Ziomek C. The first biopharmaceutical from transgenic

animals: ATryn. Modern Biopharmaceuticals 2005;995-1016.11-15

The only way to keep your health is to eat what you don't want, drink what you don't like, and do what you'd rather not -Mark Twain

THANK YOU