Bleeding response induced by anti-thrombotic doses of a phosphoinositide 3-kinase (PI3K)-β inhibitor in mice.

Abstract

INTRODUCTION:

Published evidence suggests that phosphoinositide 3 kinase-β (PI3K-β) plays an important role in platelet aggregation and shear activation. TGX-221 is a selective PI3K-β inhibitor with a good separation of anti-thrombotic efficacy and bleeding (therapeutic index) in rats. Our goal was to further evaluate potential of a PI3K-β inhibitor as an anti-thrombotic agent by determining the therapeutic index in another species and efficacy model. Reported effects of TGX-221 in rats were also confirmed.

MATERIALS AND METHODS:

TGX-221 (0.3 + 0.3, 1 + 1, 3 + 3 mg/kg + mg/kg/hr, i.v.) or vehicle was given to mice starting 15 min prior to FeCl(3) arterial thrombosis (AT), tail or kidney bleeding time (BT) procedures.

RESULTS:

Integrated blood flow over 30 min (%baseline mean ± SEM) improved (p < 0.05) with TGX-221 doses 1 + 1 (49 ± 13.9%) and 3+3 (88 ± 10.6%) versus 0.3 + 0.3 (10 ± 0.8%) and vehicle (10 ± 0.6%). Vascular patency (non-occluded/total arteries) improved (p < 0.01) with TGX-221 doses of 3 + 3 (7/8), but not 0.3 + 0.3 (0/8) or 1 + 1 (4/8) versus vehicle (0/8). Tail BT (sec) increased (p < 0.05) with TGX-221 doses of 3 + 3 (median 1560) and 1 + 1 (1305) versus vehicle (225). Mean renal BT (sec) increased (p < 0.05) in all TGX-221 groups (3 + 3: 510 + 26; 1 + 1: 478 + 41; 0.3 + 0.3: 246 + 37) versus vehicle (123 + 9). For comparison, a reference agent, aspirin (30 mpk, i.p.) increased tail BT 1.9X and renal BT 2.6X.

CONCLUSIONS:

The novel finding of a clear impact on hemostasis by TGX-221 was demonstrated by increased bleeding in two models in mice at anti-thrombotic doses. The results suggest a narrower therapeutic index for this PI3K-β inhibitor than previously recognized, at least for this species.

• Authors: J Eileen Bird, Patricia L Smith, Jeffrey S Bostwick, Petia Shipkova, William A Schumacher
• Journal: Thrombosis research (Thromb Res) Vol. 127 Issue 6 Pg. 560-4 (Jun 2011) ISSN: 1879-2472 [Electronic] United States
• PMID: 21396684 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Fibrinolytic Agents
• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidinones
• TGX 221

Topics

• Animals
• Bleeding Time
• Blood Platelets (drug effects)
• Carotid Artery Thrombosis (blood, drug therapy, enzymology)
• Disease Models, Animal
• Fibrinolytic Agents (blood, pharmacology, toxicity)
• Hemorrhage (chemically induced)
• Humans
• Kidney (blood supply)
• Male
• Mice
• Mice, Inbred C57BL
• Morpholines (blood, pharmacology, toxicity)
• Phosphatidylinositol 3-Kinases (blood)
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidinones (blood, pharmacology, toxicity)
• Rats
• Rats, Sprague-Dawley
• Tail (blood supply)