STROKEPrepared by: Cheok Ken Yew

Chan Sook Yeen Kaveeta Pergas

Lai Shu Mei Mabel Cheong Sook Ling

STROKEglobal epidemic neurological deficit diseasethird leading cause of death in Malaysia and

worldwide52000 Malaysians suffered strokes annuallysix new cases every hourcaused by insufficient blood supply to the brain

or hemorrhage into brain tissue2 main types:

- ischemic stroke

- hemorrhagic stroke

Symptoms: 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.

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 aspirin within 48 hours of onset

Reperfusion of ischemic brain 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 tissue-type 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

Aspirin Start aspirin within 48 hours of stroke onset. Use aspiring within 24 hours of rt-Pa is not recommended

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

Neuroprotective agents 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

Acute Treatment of Ischemic Stroke

SECONDARY PREVENTION

Antiplatlet therapy -Aspirin, Clopidogrel, Ticlopidine, Dipyridamole

Anticoagulants- Warfarin

Anti-hypertensive treatment -ACEI’s , ARB’s

Lipid lowering agents -Statins

Better glycaemic control in diabetes and smoking cessation

TREATMENT RECOMMENDATION

Antiplatelets:SINGLE AGENTS:•Aspirin

Alternatives:•Clopidogrel

•Ticlopidine

DOUBLE THERAPY:Addition of Clopidogrel to Aspirin

-75mg to 325mg daily.

-75 mg daily.

-250mg twice a day.

-In selected high risk patients only when benefit outweighs risk

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

TREATMENT RECOMMENDATION

Lipid lowering Lipid reduction should be considered in all subjects with previous ischaemic strokes.

Diabetic control All diabetic patients with a previous stroke should improve glycaemic control.

Cigarette smoking All smokers should stop 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 platelet’s 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/prevention-

what_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.

Schröder H. and Schrör 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: 81–106.

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 RivaroxabanInhibit thromboxane A2 Inhibit Factor Xa

Bio-availability 50-80%

Bio-availability 80-100%

Proven to be effective for stroke.

On going clinical trials.

Aspirin RivaroxabanGastric irritation & kidney impairment.

Hepatic impairment.

RM 30 per month RM 618 per month

Contraindication : Asthma Contraindication : Lactose intolerance

Rivaroxaban vs Warfarin

• Outcome Rivaroxaban Warfarin

Vascular death, stroke, embolism

3.11 3.63

Hemorrhagic stroke 0.26 0.44

Ischemic stroke 1.34 1.42

Rivaroxaban vs Warfarin

Outcome Rivaroxaban Warfarin

Major bleeding 3.60 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 wasn’t 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.

TICAGRELOR (BRILIQUETM)

Presented by: Mabel Cheong Sook Ling

01BP-200804-00013

INTRODUCTION 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).

MECHANISM OF ACTION 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.

PHARMACOLOGIC PROFILE 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).

COMPARISON OF ASPIRIN AND TICAGRELOR

Feature Aspirin Ticagrelor

Indication MI prophylaxisMild to moderate pain and feverAcute and chronic musculoskeletal conditions and rheumatic disorders

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

Mechanism of action

Irreversibly binds to COX-1 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

Efficacy in stroke prevention

22% risk reduction Reduces recurrence rate and improving survival.

1.3% death reduction

Feature Aspirin Ticagrelor

Absorption Absorbed from stomach and small intestine

Absorption affected by food

Absorbed throughout the small intestine but absorption reduces further down the GI tract

Absorption not affected by food

Bioavailability 40% - 50% 36%

Metabolism Primary metabolite: salicylic acid(hydrolysis by esterases in gastrointestinal mucosa and plasma)

Undergo extensive metabolism to produce a total of 10 metabolites

Excretion Urine Urine and faeces

Feature Aspirin Ticagrelor

Side effect Gastrointestinal, intracerebral and other bleedings, bronchospasm

Bleeding events, dyspnea, headache, epistaxis

Dosage form Tablet, caplet and coated tablet

Film-coated tablet

COMPARISON OF TICAGRELOR AND OTHER DRUGS 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.

CRITICAL APPRAISAL OF TICAGRELOREfficacy of ticagrelor

Ticagrelor demonstrated a clear beneficial treatment effect for the prevention of cardiovascular death and myocardial infarction.

It does not provide significant treatment effect on the prevention of stroke death.

SAFETY ASPECT The most important safety indicator for

anticoagulants and antiplatelets - risk of bleeding: similar level for ticagrelor as with clopidogrel (for major and death/life-threatening bleedings)

Specific bleedings or cases are associated with a higher bleeding risk.

Adverse events include dyspnea, arrhythmic effect, increased uric acid, higher serum creatinine.

CONVENIENCE & COST ASPECT 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 quality-adjusted 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.

CONCLUSION 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.

REFERENCESEuropean Medicines Agency (2011) Assessment Report for

Brilique. London: EMA.

Health Economics Substudy of PLATO Shows BRILIQUE to be a

Cost Effective Remedy Versus Generic Clopidogrel (2011) [online].

Available: http://www.pharmaceutical-networking.com/health-

economics-substudy-of-plato-shows-brilique-to-be-a-cost-effective-

remedy-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

Effects [online]. Available:

http://www.mims.com/USA/drug/info/aspirin/?type=full&mtype=generic#Dosage

[Accessed 22 May 2011].

THANK YOU

“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

PRADAXAfor stroke management

presented by Caren ChanID. No: 15719547

PRADAXA Classifications: Hematological agent; anticoagulant; thrombin inhibitor

Generic Name: Dabigatran etexilate Manufacturer: Boehringer Ingelheim

•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)

Administration may be taken with or without food but is intended to swallow whole, do not chew/crush

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

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

On the other hand, Pradaxa has fewer drug interactions and routine monitoring is not required

Description

However, there is no specific antidote for dabigatran in case of major bleeding

Dabigatran is the first oral anticoagulant available

since the approval of warfarin over 50 years ago

Dabigatran (Pradaxa) was approved in Octorber 2010

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

Description

Mechanism of ActionDabigatran 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

After oral absorption, it is metabolized by esterases to its four competitive active acyl glucoronides, active moieties

Dabigatran is eliminated primarily in the urine

Dabigatran half-life is 12-17 hours

Bleeding is the most relevant side effect of Pradaxa; indigestion, upset stomach, or burning, stomach pain

Contraindicated in severe renal imparied patients (CrCl <30 mL/min); active bleeding; hepatic impairment or liver disease

Pharmacologic Profile

Neonates, Infants, Children, and Adoloscents: Safety and efficacy have not been established

Pregnancy category C. No clinical data on exposed pregnancies are available. The potential risk for humans is unknown.

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

Pharmacologic Profile

Packing/PricePradaxa 75 mg x

30's (RM393.75)Pradaxa 110 mg x

30's (RM393.75)BottleBlisterStore at 15°C to

30°C. After opening the bottle, use Pradaxa within 30 days.

Safely throw away any unused Pradaxa after 30 days. Protect from moisture.

Properties Aspirin Pradaxa Active metabolite Salicylate Dabigatran Use/Indication Prophylaxis stroke management Mechanism Platelet COX (potently

COX-1) enzymes inhibitor.Dabigatran and its acyl glucoronides compete directly to inhibit thrombin. Preventing thrombus formation thus, absence of thrombin-induced platelet aggregation.

Anti-inflammatory effects

Yes No

Site of metabolism Liver, plasma, erythrocytes, and synovial fluid

Liver

Metabolic enzymes Carboxyesterases Esterase - catalyzed hydolysisDaily maintenance dose

75mg once daily with food 150mg twice daily

t1/2 (half-life) 15-20 minutes (aspirin)Salicylate: 2-3 hours (low dose salicylate)15-30 hours (high dose salicylate)

12-17 hours

Time for peak conc. (min)

60-120 mins (uncoated tablets)*varies with different dosage forms

60 (fasting) – 120 (high-fat meal)

Comparison between aspirin and pradaxa

Properties Aspirin Pradaxa Bleeding risk Moderate Severe

Administration With food With / Without food. Swallow whole. Do not crush or chew

Resistance Yes Unknown

Used for stroke Yes Yes

Pediatric use Yes Unknown

Pregnancy category C (D – third trimester) C (inadequate studies in pregnant women)

Dosage form (s) Oral tablets ,capsule, gum; Suppositories

Capsules

Storage Room temperature, avoid excessive heat and humidity- Oral (15-25ºC)

- Rectal (2-15ºC)

Unit bottle of 60 capsules - Once opened, product must

be used within 30 daysBlister package containing 60 capsules (10 x 6 capsule blister cards)*FDA special storage and handling requirement

Comparison between aspirin and pradaxa

Critical appraisal of the new drugBesides aspirin’s antiplatelet activity, higher dosages

of aspirin (1.3 g/day) may decrease vascular plasminogen activator, thereby increase thrombus formation – stroke

Aspirin dose of 75 to 325 mg/day were effective in secondary stroke prevention indefinitely

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%

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

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 drugDabigatran is a potent, synthetic, reversible, non-

peptide thrombin inhibitor150mg twice dailyCompared with warfarin, dabigatran etexilate is 10-

30 times more expensiveClinically, warfarin is used to prevent and treat

thromboembolic disease with various clinical condition

Dabigatran reduces stroke risk to an even greater extent than warfarin. However, as to replace warfarin to dabigatran in stroke management is still questionable

The INR test is relatively insensitive to the activity of dabigatran and may or may not be elevated with Pradaxa

Among these three drugs, warfarin requires the most aggressive monitoring (in case of bleeding), followed by aspirin then dabigatran

Clinical Comparison ReportAspirin Warfarin Dabigatran

Can be used for atrial fibrillation?

No Yes Yes

Can be used for ischemic stroke?

Yes No No

Can be used for stroke prophylaxis?

Yes Yes Yes

Can be used for TIA (transient ischemic attack)?

Yes No No

Is contraindicated in or should be used cautiously in stroke?

No Yes No

Aspirin Warfarin DabigatranIs contraindicated in or should be used cautiously in GI bleeding?

Yes Yes No

Is it contraindicated in or should be used cautiously in bleeding?

No Yes Yes

Packing/Pricing 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

Clinical Comparison Report

ConclusionPradaxa may emerge as a new intervention, but its current

status of studies is insufficient for confidence as drug of choice for stroke management

RE-LY study reported that Pradaxa 150mg twice daily significantly reduced ischemic and hemorrhagic strokes relative to warfarin

My personal view would be for the use of aspirin as prophylaxis stroke management which is relatively lower cost of pharmaceutical approaches, minimized bleeding risk by lowering the optimum dosage, patient compliance test, until further studies conducted on Pradaxa, proving confidence as

alternative drug of choice

The only “attraction” Pradaxa bought about is requiring no aggressive monitoring compare to other anticoagulants

Hence, appropriate and thorough studies on therapy regime may reduce stroke morbidity and mortality

References 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.

Clinical Pharmacology.(2011) Elsevier. [online]: http://0-clinicalpharmacology-ip.com.alpha2.latrobe.edu.au/default.aspx

Pradaxa Prescribing Information. Drug Infromation Online. Drugs.com.(2010) [online]: http://www.drugs.com/pro/pradaxa.html

Eline A. Et al. (2010) New Drug Mechanism. Dabigatran etexilate. BJCP:70:1;14-15.

Safety Information. U.S. Food and Drug Administration. (2011) [online]: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm249005.htm

THANK YOUTake 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 ReportFormulation C

(Individual Presentation)

ATrynBy,

Kaveeta PergasBP01-200904-00032

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 2-8°C

CONTRAINDICATIONS:-Hypersensitivity to goat and goat milk proteins. [4] WARNING & PRECAUTIONS:-Anaphylaxis and severe hypersensitivity reactions

are possible.-Coagulation Monitoring TestDRUG INTERACTIONS:-Heparin or other anticoagulantsADVERSE REACTIONS:-Hemorrhage

USE IN SPECIFIC POPULATIONS-Pregnancy-Nursing mothers

Atryn does not contain anypreservatives nor is it formulatedwith human plasma proteins

NOTE!!!

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 peri-partum 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 ATRYN

Anti platlet Antithrombin (Recombinant)

Cheap Expensive

Oral (Diluted in water or chewed) IV

Hypersensitivity to salicylates Hypersensitive to goat products

Aspirin works as a blood thinner, helping

to prevent the further formation of stroke-

causing clots.

Atryn works by regulating the clotting

and inflammatory processes that lead to

the formation of blood clots.

Produced from drug active ingredients Produced from transgenic goats

Hemorrhagic stroke. While daily aspirin

can help prevent a clot-related stroke, it

may increase the risk of a bleeding stroke.

 Potential safety issue is the development

of an immunological reaction to the

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 DISADVANTAGES

• Capacity • Time

• Scale • Animal Ethics

• Harvesting • Lactation

ConclusionOver 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