Download - Stroke (Drug Research)
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STROKEPrepared by: Cheok Ken Yew
Chan Sook Yeen Kaveeta Pergas
Lai Shu Mei Mabel Cheong Sook Ling
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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
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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.
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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
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algorithm for treatment options in stroke
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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
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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
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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
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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
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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
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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
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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.
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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.
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ASPIRIN
Prevent serious vascular events in stroke survivor,
Reduce stroke recurrence
Improve survival rate
Cost effective
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ASPIRIN DRAWBACKS
Bleeding
Not for asthma
Renal impairment
Pregnancy Class C
CI for children <16 yrs
Gastrointestinal problems
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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.
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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.
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RIVAROXABAN
BY
CHEOK
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Rivaroxaban
• Xarelto (Brand name)
• Available in 10 mg oral dose.
• Taken once daily.
• Antiplatelets &(Thrombolytics) agent
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Indications
• Prevent venous thromboembolism (VTE) in hip and knee surgery.
• Prevent strokes due to atrial fibrillation.
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MOA
• Inhibition of Factor Xa.
• Prothrombin cannot convert to thrombin.
• No fibrin clot formed and activation of platelets.
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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.
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Adverse reactions
• Hepatic impairment
• Occult bleeding in organ and
tissues
• Post-operative anemia
• Wound healing complications
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Contraindications
• Hepatic and renal impairment.
• Children <18 yr.
• Pregnancy & lactation.
• High bleeding risk.
• Lactose intolerance.
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Usage for stroke
• Study still in Phase 3 trials.
• Not approved by FDA
• Stroke occurrence lesser than
warfarin.
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•
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.
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Aspirin RivaroxabanGastric irritation & kidney impairment.
Hepatic impairment.
RM 30 per month RM 618 per month
Contraindication : Asthma Contraindication : Lactose intolerance
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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
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Rivaroxaban vs Warfarin
Outcome Rivaroxaban Warfarin
Major bleeding 3.60 3.45
INR monitoring NO YES
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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
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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.
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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.
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TICAGRELOR (BRILIQUETM)
Presented by: Mabel Cheong Sook Ling
01BP-200804-00013
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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).
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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.
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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%.
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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).
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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
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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
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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
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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.
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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.
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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.
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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.
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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.
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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].
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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
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PRADAXAfor stroke management
presented by Caren ChanID. No: 15719547
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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)
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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)
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Drug Research ReportFormulation C
(Individual Presentation)
ATrynBy,
Kaveeta PergasBP01-200904-00032
Bachelor of Pharmacy
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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
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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.
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Transgenic Goats
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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
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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
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USE IN SPECIFIC POPULATIONS-Pregnancy-Nursing mothers
Atryn does not contain anypreservatives nor is it formulatedwith human plasma proteins
NOTE!!!
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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.
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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.
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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.
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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
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• 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
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• 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.
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ADVANTAGES DISADVANTAGES
• Capacity • Time
• Scale • Animal Ethics
• Harvesting • Lactation
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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.
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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
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“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