cangrelor and Arterial-Occlusive-Diseases

An important role for adenosine diphosphate (ADP)-induced platelet activation and aggregation was proposed more than 40 years ago. The clinical use of clopidogrel, a prodrug of an irreversible P2Y (12) antagonist, has further proved the relevance of inhibiting signaling via the platelet-specific P2Y (12) ADP receptor in the prevention of cardiovascular events. Pharmacological studies at AstraZeneca R&D Charnwood have identified direct, selective, and competitive P2Y (12) antagonists, including cangrelor (also known as AR-C69931MX), which is suitable for intravenous administration, and AZD6140, which is suitable for oral administration. In preclinical use, these compounds predictably and effectively inhibited platelet aggregation without significant increases in bleeding time. In clinical use, these compounds may have significant advantages over current antiplatelet agents. This article summarizes preclinical and clinical data on cangrelor and AZD6140 and discusses the potential of these compounds as novel antiplatelet therapies.

Topics: Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Administration, Oral; Animals; Arterial Occlusive Diseases; Clinical Trials as Topic; Dogs; Double-Blind Method; Drug Evaluation, Preclinical; Female; Fibrinolytic Agents; Humans; Injections, Intravenous; Male; Membrane Proteins; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Pyridines; Rabbits; Randomized Controlled Trials as Topic; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor

In cases of large-vessel-occlusion strokes due to an underlying tandem internal carotid artery occlusion or intracranial atherosclerotic disease, concomitant stent placement may be needed. Immediate platelet inhibition is necessary, but to date, a standardized approach for antiplatelet inhibition in acute settings is still missing. Here we report our single-center experience about the safety and efficacy of periprocedural administration of cangrelor in patients with acute ischemic stroke due to intracranial or cervical artery occlusion undergoing stent placement.. We retrospectively evaluated all cases of acute ischemic stroke that needed acute stent implantation and were treated with periprocedural administration of cangrelor between January 2019 and April 2020 at our institution. All patients who needed either extracranial or intracranial artery stent placement (in either the anterior or posterior circulation) were included.. We evaluated 38 patients in whom cangrelor was administered IV periprocedurally. Their mean age was 64 years (range, 26-85 years), with 25/38 male subjects and 13/38 female patients. In 26 patients (68.4%), a tandem occlusion was present and was treated with carotid artery stent placement, while 12 patients (31.6%) required an intracranial stent implantation. In 4 subjects (10.5%), an intracerebral hemorrhage occurred after the procedure. All patients in the series were alive 1 week after the procedure.. Although larger, multicentric randomized studies are strongly warranted, our results support the hypothesis of a possible role of cangrelor as a valuable therapeutic option in the management of platelet inhibition in acute ischemic stroke procedures after intra- or extracranial stent placement.

Topics: Adenosine Monophosphate; Adult; Aged; Aged, 80 and over; Arterial Occlusive Diseases; Carotid Artery, Internal; Cerebral Hemorrhage; Endovascular Procedures; Female; Humans; Ischemic Stroke; Male; Middle Aged; Platelet Aggregation Inhibitors; Retrospective Studies; Stents; Thrombectomy; Treatment Outcome

P2Y1, P2X1, and P2T receptors mediate ADP-induced platelet aggregation. The antithrombotic effects of AR-C69931MX (N6-[2-methylthio)ethyl]-2-[3,3,3-trifluoropropylthio]-5'-adenylic acid, monoanhydride with dichloromethylenebiphosphonic acid), a selective P2T platelet receptor antagonist, was assessed in a canine model of arterial thrombosis. Placebo or AR-C69931MX (4.0 microg/kg/min for 6 h) pretreatment was administered as an intravenous infusion beginning 15 min before inducing vessel wall injury. A 300-microA anodal current was applied to the intima of the carotid artery for 180 min or discontinued 30 min after cessation of blood flow due to thrombus formation. Each of five control animals developed occlusive thrombi within 3 h after induction of vessel wall injury. In contrast, carotid artery blood flow in five of six AR-C69931MX-treated animals was maintained for the duration of the protocol. Ex vivo platelet aggregation in response to adenosine diphosphate was inhibited at the first measurement time point of 75 min after the start of drug infusion and remained inhibited during drug administration. Bleeding time values were increased in the drug-treated group. Values for both the ex vivo platelet aggregation and the bleeding times returned to control values shortly after discontinuation of AR-C69931MX. The results indicate that AR-C69931MX antagonizes the ex vivo and in vivo aggregatory actions of ADP, and displays a rapid onset and offset of action with the ability to prevent occlusive arterial thrombus formation. AR-C69931MX may be suitable for the management of patients who require short-term modulation of platelet function.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Animals; Arterial Occlusive Diseases; Bleeding Time; Blood Flow Velocity; Blood Platelets; Carotid Arteries; Carotid Artery Thrombosis; Disease Models, Animal; Dogs; Female; Hemodynamics; Injections, Intravenous; Male; Membrane Proteins; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Tunica Intima