AGGRENOXAGGRENOXTMTMDevelopment Development Rationale Rationale

Head of Haemostasis Laboratory Head of Haemostasis Laboratory Blood Transfusion Center of the German Red Cross Blood Transfusion Center of the German Red Cross

Oldenburg, GermanyOldenburg, Germany

Thomas Müller, MD, PhDThomas Müller, MD, PhD

Haemostatic RepairHaemostatic Repair

Mural Thrombus FormationMural Thrombus Formation

Blood Blood SampleSample

(anticoagulated)(anticoagulated)

FlowFlow

Formation of Formation of Platelet AggregatesPlatelet Aggregates

Platelet Aggregates Form Under Platelet Aggregates Form Under Flow on Subendothelial MatrixFlow on Subendothelial Matrix

Müller et al. (1990) Müller et al. (1990) Br J Clin Pharmac.Br J Clin Pharmac.

Inhibition of the GrowthInhibition of the Growthof All Aggregatesof All Aggregates

Müller et al. (1990) Müller et al. (1990) Br J Clin Pharmac.Br J Clin Pharmac.

40 40

PlaceboPlacebo ER-DPER-DP400 mg/d400 mg/d

ASAASA50 mg/d50 mg/d

ASA/ER-DPASA/ER-DP50 mg + 50 mg + 400 mg/d400 mg/d

0 0

20 20

60 60

80 80

Relative Relative Reduction Reduction

in Mean Area of in Mean Area of

ALLALLThrombi (%)Thrombi (%) N = 23N = 23

N = 22N = 22

N = 23N = 23

N = 24N = 24

Inhibition of the GrowthInhibition of the Growthof Very Large Aggregatesof Very Large Aggregates

2 2

PlaceboPlacebo ER-DPER-DP400 mg/d400 mg/d

ASAASA50 mg/d50 mg/d

ASA/ER-ASA/ER-DPDP

50 mg + 50 mg + 400 mg/d400 mg/d

0 0

1 1

3 3

4 4

Reduction ofReduction ofVERY LARGE VERY LARGE

ThrombiThrombi

Müller et al. (1990) Müller et al. (1990) Br J Clin Pharmac.Br J Clin Pharmac.

Mural Thrombus FormationMural Thrombus Formation

AA TxA2

Cyclooxygenase Generates Cyclooxygenase Generates Thromboxane AThromboxane A22

Weksler B et al. (1985) Weksler B et al. (1985) Stroke.Stroke. 16:1–9. 16:1–9.

AA TxA2

AA

ASA Irreversibly Inhibits ASA Irreversibly Inhibits CyclooxygenaseCyclooxygenase

40 mg ASA/d in stroke patients40 mg ASA/d in stroke patients

X

CollagenCollagen

ThrombinThrombin

ShearShear

AdrenalineAdrenaline

PAFPAF

TxATxA22

ADPADP

??

Platelet Activation AggregationPlatelet Activation Aggregation

X

ASA Inhibits Only a Single ASA Inhibits Only a Single of Multiple Pathwaysof Multiple Pathways

AdenosineAdenosine

ADP is Degraded to AdenosineADP is Degraded to Adenosine

ADPADP

ADPADPAdenosineAdenosine

PlateletPlateletInhibitionInhibitionX

DP Inhibits the Adenosine UptakeDP Inhibits the Adenosine UptakeICIC5050 = 0.25 µg/mL Human Plasma = 0.25 µg/mL Human Plasma

Extended Release DipyridamoleExtended Release Dipyridamole

44 88 121200

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

DPDP PlasmaPlasma Conc.Conc.

(µg/mL)(µg/mL)

Time (hours)Time (hours)

Summary and ConclusionsSummary and Conclusions

Dipyridamole and ASA inhibit platelet Dipyridamole and ASA inhibit platelet aggregation by independent mechanismsaggregation by independent mechanisms

Doses and formulationsDoses and formulations

No evidence for pharmacokinetic interactionNo evidence for pharmacokinetic interaction

Summary and ConclusionsSummary and Conclusions

Dipyridamole and ASA inhibit platelet Dipyridamole and ASA inhibit platelet aggregation by independent mechanismsaggregation by independent mechanisms

Doses and formulations optimizedDoses and formulations optimized

No evidence for pharmacokinetic interactionNo evidence for pharmacokinetic interaction

Combining ASA with DP in AGGRENOXCombining ASA with DP in AGGRENOXTMTM

Additive inhibition of platelet thrombus formationAdditive inhibition of platelet thrombus formation