Elinogrel potassium

Here, we report the in vitro characterization of the P2Y12 receptor antagonist selatogrel (ACT-246475). Binding studies with radiolabeled selatogrel demonstrated that selatogrel is a competitive antagonist of ADP binding to the P2Y12 receptor with a fast onset of action. Consequently, selatogrel was confirmed to be a potent inhibitor of P2Y12-mediated intra-platelet signaling and ADP-induced platelet activation. Characterization of selatogrel in platelet-rich plasma in vitro demonstrated that the mode of anti-coagulation affected the anti-platelet potency. Specifically, in platelet-rich plasma containing physiological calcium concentration (anticoagulated with a direct thrombin inhibitor), selatogrel achieved half-maximal inhibition of ADP-induced platelet aggregation at a 3-fold lower concentration than in conditions with low calcium concentration (anticoagulated with citrate). Furthermore, calcium-dependent reduction in selatogrel potency was observed in whole blood platelet aggregation using the VerifyNow™ system with a 3.7-fold potency loss in low calcium conditions. A comparable potency loss was also observed with the reversible P2Y12 receptor antagonists ticagrelor, cangrelor and elinogrel. Furthermore, receptor-binding experiments using radiolabeled selatogrel confirmed a 3-fold lowering of selatogrel binding affinity to the P2Y12 receptor in low calcium conditions. In conclusion, our data suggest that in low calcium conditions (i.e., citrate-anticoagulated blood), there is a risk of underestimating the potency of reversible P2Y12 receptor antagonists. To avoid overdosing, and a potential increase in bleeding risk, we propose that the ex vivo evaluation of reversible P2Y12 receptor antagonists should be performed with platelet assay systems containing physiological calcium concentration.

Acetylsalicylic acid, clopidogrel and cilostazol are well-established agents inhibiting the normal function of platelets with known advantages and limitations. The development of novel antiplatelet agents aims to provide equal or superior outcomes for patients and simultaneously minimize side effects.

The aim of this manuscript is to review the latest data on the use of novel antiplatelet agents in vascular patients.

Based on our 2016 review, a further search in the English medical literature has yielded a number of publications on cangrelor, prasugrel, ticagrelor, vorapaxar and a number of other – still experimental – agents (Ir- 6, UBO-QIC, W1, revacept and YM-254890).

Recently published data have not altered the use and indications of cangrelor, prasugrel and vorapaxar; all of them now approved by both FDA and EMA. The EUCLID trial has recently provided valuable data on the clinical use of ticagrelor, although results regarding vascular patients and administration of ticagrelor are still under scrutiny. Vorapaxar remains the only novel antiplatelet that is approved for PAD. Randomized control trials that focus on vascular patients are necessary to establish the safety and efficacy of these novel agents. Despite their positive initial results, most novel experimental antiplatelets are still in early development, thus in preclinical or early clinical phases of their trials. Research on three novel antiplatelets is currently discontinued (atopaxar, darexaban and elinogrel).

Vorapaxar remains the only novel antiplatelet that is approved for PAD. Other novel antiplatelets demonstrate positive results, but further studies focused on vascular patients are necessary. Novel experimental antiplatelets are still in the early phases of the clinical and preclinical studies.