Pharmacokinetic/pharmacodynamic assessment of a novel, pharmaceutical lipid-aspirin complex: results of a randomized, crossover, bioequivalence study.

Aspirin (acetylsalicylic acid, ASA) can lead to gastrointestinal mucosal injury through disruption of its protective phospholipid bilayer. A liquid formulation of a novel pharmaceutical lipid-aspirin complex (PL-ASA) was designed to prevent this disruption. We sought to determine the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of PL-ASA compared with immediate release aspirin (IR-ASA). In this active-control crossover study, 32 healthy volunteers were randomized to receive 1 of 2 dose levels (a single dose of 325 mg or 650 mg) of either PL-ASA or IR-ASA. After a 2-week washout period between treatment assignments, subjects received a single dose of the alternative treatment, at the same dose level. The primary objectives of the study were to assess, for PL-ASA and IR-ASA at 325 mg and 650 mg dose levels, PK and PD bioequivalence, and safety, over a 24-h period after administration of both drugs. PK parameters were similar for PL-ASA and IR-ASA, and met FDA-criteria for bioequivalence. Regarding PD, both drugs also showed Cmin TxB2 values below 3.1 ng/mL (cut-off associated with decreased cardiovascular events) and > 99% inhibition of serum TxB2 ( ≥ 95% inhibition represents the cut-off for aspirin responders) along with similar results in several secondary PK/PD parameters. There were no serious adverse events or changes from baseline in vital signs or laboratory values in either of the 2 treatment groups. PL-ASA's novel liquid formulation has similar PK and PD performance compared with IR-ASA, supporting functional and clinical equivalence. These data coupled with the improved gastric safety of PL-ASA suggest that this novel formulation may exhibit an improved benefit-risk profile, warranting evaluation in future trials.Clinical trial registration: http://www.clinicaltrials.gov . Unique Identifier: NCT04008979.

Impaired integrin ß3 delays endothelial cell regeneration and contributes to arteriovenous graft failure in mice.

OBJECTIVE: Neointima formation is associated with stenosis and subsequent thrombosis in arteriovenous grafts (AVGs). A role of integrin ß3 in the neointima formation of AVGs remains poorly understood. APPROACH AND RESULTS: In integrin ß3(-/-) mice, we found significantly accelerated occlusion of AVGs compared with the wild-type mice. This is caused by the development of neointima and lack of endothelial regeneration. The latter is a direct consequence of impaired functions of circulating angiogenic cells (CACs) and platelets in integrin ß3(-/-) mice. Evidence suggests the involvement of platelet regulating CAC homing to and differentiation at graft sites via transforming growth factor-ß1 and Notch signaling pathway. First, CACs deficient of integrin ß3 impaired adhesion activity toward exposed subendothelium. Second, platelets from integrin ß3(-/-) mice failed to sufficiently stimulate CACs to differentiate into mature endothelial cells. Finally, we found that transforming growth factor-ß1 level was increased in platelets from integrin ß3(-/-) mice and resulted in enhanced Notch1 activation in CACs in AVGs. These results demonstrate that integrin ß3 is critical for endothelial cell homing and differentiation. The increased transforming growth factor-ß1 and Notch1 signaling mediates integrin ß3(-/-)-induced AVG occlusion. This accelerated occlusion of AVGs was reversed in integrin ß3(-/-) mice transplanted with the bone marrow from wild-type mice. CONCLUSIONS: Our results suggest that boosting integrin ß3 function in the endothelial cells and platelets could prevent neointima and thrombosis in AVGs.