Antiplatelet Agents in Acute Coronary Syndromes

Sakhuja, Rahul; Yeh, Robert W.; Bhatt, Deepak L.

doi:10.1016/j.cpcardiol.2009.11.002

Cited by 17 publications

(10 citation statements)

References 164 publications

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“…It is important to emphasize that the effects of anti‐platelet drugs in patients with STEMI cannot be directly extrapolated from the results known for stable patients, as the former have greater variability in the absorption and response to these agents . Also, factors such as age, obesity and polypharmacotherapy in acute patients may also influence the onset and final effects of drug action .…”

Section: Discussionmentioning

confidence: 99%

Upstream clopidogrel, prasugrel, or ticagrelor for patients treated with primary angioplasty: Results of an angiographic randomized pilot study

Mont'Alverne-Filho

Rodrigues-Sobrinho

Medeiros

et al. 2015

Cathet Cardio Intervent

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Section: Discussionmentioning

confidence: 99%

Upstream clopidogrel, prasugrel, or ticagrelor for patients treated with primary angioplasty: Results of an angiographic randomized pilot study

Mont'Alverne-Filho

Rodrigues-Sobrinho

Medeiros

et al. 2015

Cathet Cardio Intervent

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“…TϩI, combination of tirofiban and idraparinux. Bar, 100 m. Sakhuja et al, 2010). Likewise, in patients requiring both antiplatelet and anticoagulant therapy, the limitation is the bleeding risk (Schulman and Spencer, 2010).…”

Section: Discussionmentioning

confidence: 99%

The Antithrombotic Activity of EP224283, a Neutralizable Dual Factor Xa Inhibitor/Glycoprotein IIbIIIa Antagonist, Exceeds That of the Coadministered Parent Compounds

Hechler¹,

Freund²,

Alame³

et al. 2011

The Journal of Pharmacology and Experimental Therapeutics

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EP224283 combines in a single molecule idraparinux and tirofiban, which allows obtaining a predictable and sustained antiplatelet effect through the transfer of the pharmacokinetics properties of idraparinux to the anti-␣IIb␤3 antagonist. The activity can be instantaneously neutralized by injection of avidin, a specific antidote. We have tested the effects of this new profile anticoagulant in various thrombosis models. The antithrombotic effect of EP224283 was compared with those of the parent compounds used alone or in association at doses achieving low to moderate inhibition of platelet aggregation ex vivo. In a model of systemic thromboembolism independent of thrombin generation, tirofiban and EP224283 had similar effects at equimolar doses. On the other hand, EP224283 was more potent than tirofiban or idraparinux under thrombin-dependent conditions. In a ferric chloride-induced thrombosis model, EP224283 was more potent than either parent compound or their combination. Similar results were obtained after atherosclerotic plaque rupture in ApoE(Ϫ/Ϫ) mice. Thus, the dual action of EP224283 exceeds that of the parent compounds used in combination. A possible explanation is that EP224283 could concentrate antithrombin inside the thrombus by binding to ␣IIb␤3 through the tirofiban moiety, as shown by immunolabeling of the occluded vessel. No prolongation of the bleeding time was observed at doses achieving strong antithrombotic effects, suggesting that low to moderate ␣IIb␤3 inhibition combined with factor Xa inhibition minimizes the bleeding risk. The favorable antithrombotic profile of EP224283 together with its possible neutralization by avidin makes it an interesting drug candidate for the treatment and prevention of acute ischemic events.

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“…Drugs that affect platelet function are a fundamental approach in the management of ACS. 4 Food and Drug Administration (FDA)-approved drugs such as ticlopidine, clopidogrel, prasugrel, and ticagrelor are antagonists of purinergic P2Y12 receptor, through which ADP elicits platelet aggregation. 5 , 6 Fibrinogen receptor αΙΙbβ3 integrin plays a significant role in platelet adhesion and aggregation.…”

Section: Introductionmentioning

confidence: 99%

Vipegitide: a folded peptidomimetic partial antagonist of α2β1 integrin with antiplatelet aggregation activity

Momić¹,

Katzhendler²,

Shai³

et al. 2015

DDDT

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Linear peptides containing the sequence WKTSRTSHY were used as lead compounds to synthesize a novel peptidomimetic antagonist of α2β1 integrin, with platelet aggregation-inhibiting activity, named Vipegitide. Vipegitide is a 13-amino acid, folded peptidomimetic molecule, containing two α-aminoisobutyric acid residues at positions 6 and 8 and not stable in human serum. Substitution of glycine and tryptophan residues at positions 1 and 2, respectively, with a unit of two polyethylene glycol (PEG) molecules yielded peptidomimetic Vipegitide-PEG2, stable in human serum for over 3 hours. Vipegitide and Vipegitide-PEG2 showed high potency (7×10−10 M and 1.5×10−10 M, respectively) and intermediate efficacy (40% and 35%, respectively) as well as selectivity toward α2 integrin in inhibition of adhesion of α1/α2 integrin overexpressing cells toward respective collagens. Interaction of both peptidomimetics with extracellular active domain of α2 integrin was confirmed in cell-free binding assay with recombinant α2 A-domain. Integrin α2β1 receptor is found on the platelet membrane and triggers collagen-induced platelet aggregation. Vipegitide and Vipegitide-PEG2 inhibited α2β1 integrin-mediated adhesion of human and murine platelets under the flow condition, by 50%. They efficiently blocked adenosine diphosphate- and collagen I-induced platelet aggregation in platelet rich plasma and whole human blood. Higher potency of Vipegitide than Vipegitide-PEG2 is consistent with results of computer modeling of the molecules in water. These peptidomimetic molecules were acutely tolerated in mice upon intravenous bolus injection of 50 mg/kg. These results underline the potency of Vipegitide and Vipegitide-PEG2 molecules as platelet aggregation-inhibiting drug lead compounds in antithrombotic therapy.

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Antiplatelet Agents in Acute Coronary Syndromes

Abstract: Background-Oral

Cited by 17 publications

References 164 publications

Upstream clopidogrel, prasugrel, or ticagrelor for patients treated with primary angioplasty: Results of an angiographic randomized pilot study

Upstream clopidogrel, prasugrel, or ticagrelor for patients treated with primary angioplasty: Results of an angiographic randomized pilot study

The Antithrombotic Activity of EP224283, a Neutralizable Dual Factor Xa Inhibitor/Glycoprotein IIbIIIa Antagonist, Exceeds That of the Coadministered Parent Compounds

Vipegitide: a folded peptidomimetic partial antagonist of α2β1 integrin with antiplatelet aggregation activity

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Antiplatelet Agents in Acute Coronary Syndromes

Abstract: Background-Oral

Cited by 17 publications

References 164 publications

Upstream clopidogrel, prasugrel, or ticagrelor for patients treated with primary angioplasty: Results of an angiographic randomized pilot study

Upstream clopidogrel, prasugrel, or ticagrelor for patients treated with primary angioplasty: Results of an angiographic randomized pilot study

The Antithrombotic Activity of EP224283, a Neutralizable Dual Factor Xa Inhibitor/Glycoprotein IIbIIIa Antagonist, Exceeds That of the Coadministered Parent Compounds

Vipegitide: a folded peptidomimetic partial antagonist of &alpha;2&beta;1 integrin with antiplatelet aggregation activity

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Vipegitide: a folded peptidomimetic partial antagonist of α2β1 integrin with antiplatelet aggregation activity