Bleeding response induced by anti- XXXX doses of a phosphoinositide 3-kinase (PI3K)-b inhibitor in @entity19 .

@entity24871 @entity548 @entity1423 @entity7425 @entity19 @entity117 @entity36274 @entity35 @entity715
INTRODUCTION: Published evidence suggests that @entity7425 3 kinase-b (PI3K-b) plays an important role in @entity1423 and shear activation. @entity36274 is a selective PI3K-b inhibitor with a good separation of anti- @entity715 efficacy and @entity548 (therapeutic index) in @entity35 . Our goal was to further evaluate potential of a PI3K-b inhibitor as an anti- @entity715 agent by determining the therapeutic index in another species and efficacy model. Reported effects of @entity36274 in @entity35 were also confirmed. MATERIALS AND METHODS: @entity36274 (0.3 + 0.3, 1 + 1, 3 + 3 mg/kg + mg/kg/hr, i.v.) or vehicle was given to @entity19 starting 15 min prior to @entity24871 @entity715 ( @entity715 ), tail or kidney @entity548 time (BT) procedures. RESULTS: Integrated blood flow over 30 min (%baseline mean    SEM) improved (p < 0.05) with @entity36274 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 @entity36274 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 @entity36274 doses of 3 + 3 (median 1560) and 1 + 1 (1305) versus vehicle (225). Mean renal BT (sec) increased (p < 0.05) in all @entity36274 groups (3 + 3: 510 + 26; 1 + 1: 478 + 41; 0.3 + 0.3: 246 + 37) versus vehicle (123 + 9). For comparison, a reference agent, @entity117 (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 @entity36274 was demonstrated by increased @entity548 in two models in mice at anti- @entity715 doses. The results suggest a narrower therapeutic index for this PI3K-b inhibitor than previously recognized, at least for this species.
