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AGGRENOX TM Development Rationale

AGGRENOX TM Development Rationale . Thomas Müller, MD, PhD. Head of Haemostasis Laboratory Blood Transfusion Center of the German Red Cross Oldenburg, Germany. Haemostatic Repair. Mural Thrombus Formation. Platelet Aggregates Form Under Flow on Subendothelial Matrix. Flow. Blood

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AGGRENOX TM Development Rationale

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  1. AGGRENOXTMDevelopment Rationale Thomas Müller, MD, PhD Head of Haemostasis Laboratory Blood Transfusion Center of the German Red Cross Oldenburg, Germany

  2. Haemostatic Repair

  3. Mural Thrombus Formation

  4. Platelet Aggregates Form Under Flow on Subendothelial Matrix Flow Blood Sample (anticoagulated) Formation of Platelet Aggregates Müller et al. (1990) Br J Clin Pharmac.

  5. Inhibition of the Growthof All Aggregates 80 N = 24 N = 23 60 Relative Reduction in Mean Area of ALL Thrombi (%) 40 N = 22 20 N = 23 0 Placebo ER-DP 400 mg/d ASA 50 mg/d ASA/ER-DP 50 mg + 400 mg/d Müller et al. (1990) Br J Clin Pharmac.

  6. Inhibition of the Growthof Very Large Aggregates 4 3 Reduction ofVERY LARGE Thrombi 2 1 0 Placebo ASA/ER-DP50 mg + 400 mg/d ER-DP400 mg/d ASA50 mg/d Müller et al. (1990) Br J Clin Pharmac.

  7. Mural Thrombus Formation

  8. Cyclooxygenase Generates Thromboxane A2 TxA2 AA

  9. ASA Irreversibly Inhibits Cyclooxygenase TxA2 AA X AA 40 mg ASA/d in stroke patients Weksler B et al. (1985) Stroke. 16:1–9.

  10. ASA Inhibits Only a Single of Multiple Pathways TxA2 Collagen Thrombin Shear Adrenaline PAF X ADP ? Platelet Activation Aggregation

  11. ADP is Degraded to Adenosine ADP Adenosine

  12. DP Inhibits the Adenosine UptakeIC50 = 0.25 µg/mL Human Plasma Platelet Inhibition X ADP Adenosine

  13. Extended Release Dipyridamole 2.5 2.0 DP Plasma Conc. (µg/mL) 1.5 1.0 0.5 0 4 8 12 Time (hours)

  14. Summary and Conclusions • Dipyridamole and ASA inhibit platelet aggregation by independent mechanisms • Doses and formulations • No evidence for pharmacokinetic interaction

  15. Summary and Conclusions • Dipyridamole and ASA inhibit platelet aggregation by independent mechanisms • Doses and formulations optimized • No evidence for pharmacokinetic interaction • Combining ASA with DP in AGGRENOXTM • Additive inhibition of platelet thrombus formation

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