Application of Auxiliary VerifyNow Point-of-Care Assays to Assess the Pharmacodynamics of RUC-4, a Novel αIIbβ3 Receptor Antagonist

Bentur, Ohad S.; Li, Jihong; Jiang, Caroline S.; Martin, Linda H.; Kereiakes, Dean J.; Coller, Barry S.

doi:10.1055/s-0041-1732343

Cited by 5 publications

(4 citation statements)

References 51 publications

(64 reference statements)

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“…Previous reports indicated that both zalunfiban and selatogrel potencies differ when evaluated in TSC versus PPACK or heparin anticoagulated blood [ 27 , 30 ]. These findings have been reported for other small molecule GPIIb-IIIa antagonists that had greater inhibition levels when blood was collected in TSC anticoagulants compared to non-calcium chelating anticoagulants such as PPACK or heparin [ 31 , 32 ]. Therefore, PPACK anticoagulant was and is often recommended for PD evaluation of this drug class in clinical settings.…”

Section: Discussionsupporting

confidence: 67%

Comparison of the effects of the GPIIb-IIIa antagonist Zalunfiban and the P2Y12 antagonist Selatogrel on Platelet Aggregation

Curry¹,

Rikken

Gibson

et al. 2023

J Thromb Thrombolysis

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Understanding the pharmacodynamic effects of platelet inhibitors is standard for developing more effective antithrombotic therapies. An example is the antithrombotic treatment of acute coronary syndrome (ACS), in particular ST-elevated myocardial infarction (STEMI) patients who are in need for rapid acting strong antithrombotic therapy despite the use of aspirin and oral P2Y12-inhibitors. In this study, we evaluated two injectable platelet inhibitors under clinical development (the P2Y12 antagonist selatogrel and the GPIIb-IIIa antagonist zalunfiban) that may be amenable to pre-hospital treatment of STEMI patients. Platelet reactivity was assessed at inhibitor concentrations that represent clinically relevant levels of platelet inhibition (IC20-50%, 1/2Cmax, and Cmax). Light transmission aggregometry (LTA), was used to evaluate the initial rate of aggregation (primary slope, PS) and maximal aggregation (MA). Both adenosine diphosphate (ADP) and thrombin receptor agonist peptide (TRAP) were used as agonists. Zalunfiban demonstrated similar inhibition of platelet aggregation when blood was collected in PPACK or TSC, whereas selatogrel demonstrated greater inhibition in PPACK. In this study, using PPACK anticoagulant, selatogrel and zalunfiban affected PS in response to ADP equivalently at all drug concentrations tested. In contrast, zalunfiban had significantly greater potency at its Cmax concentration compared to selatogrel using TRAP as agonist. Upon evaluation of MA responses at lower doses, selatogrel had greater inhibition of MA in response to ADP than zalunfiban; however, at concentrations that represent Cmax, the drugs were equivalent. Zalunfiban also had greater inhibition of MA in response to TRAP at the Cmax dose. These data suggest that zalunfiban may provide greater protection in reducing thrombus formation than selatogrel, especially since thrombin is an early, key primary agonist in the pathophysiology of thrombotic events.

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Section: Discussionsupporting

confidence: 67%

Comparison of the effects of the GPIIb-IIIa antagonist Zalunfiban and the P2Y12 antagonist Selatogrel on Platelet Aggregation

Curry¹,

Rikken

Gibson

et al. 2023

J Thromb Thrombolysis

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“…The cecal ligation and double puncture (CLP) procedures were performed on under anesthesia with isoflurane (2 ± 4% induction in chamber and 1 ± 2% maintenance in mask) as described previously (26,(31)(32)(33). Following midline laparotomy, the cecum was identified, the mesentery trimmed, and the stalk joining the cecum to the large intestine ligated.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

“…PBMC were co-cultured for 3 days at 37°C in the presence or absence of LPS (1mM). To block the P2Y 12 signaling pathway in vitro, we used Ticagrelor (100mg/mL), a well-established selective P2Y 12 antagonist, which has been used in multiple in vitro studies (32,33,39,40). To block the P2Y 1 signaling pathway in vitro, we used MRS2279 (MRS, 100mg/mL), a wellestablished selective P2Y 1 antagonist, which has been used in multiple in vitro studies (41)(42)(43)(44).…”

Section: Peripheral Blood Mononuclear Cell Culture and Treatmentsmentioning

confidence: 99%

Sex-related differences in the response of anti-platelet drug therapies targeting purinergic signaling pathways in sepsis

Amoafo

Entsie²,

Albayati³

et al. 2022

Front. Immunol.

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Sepsis, a complex clinical syndrome resulting from a serious infection, is a major healthcare problem associated with high mortality. Sex-related differences in the immune response to sepsis have been proposed but the mechanism is still unknown. Purinergic signaling is a sex-specific regulatory mechanism in immune cell physiology. Our studies have shown that blocking the ADP-receptor P2Y12 but not P2Y1 receptor was protective in male mice during sepsis, but not female. We now hypothesize that there are sex-related differences in modulating P2Y12 or P2Y1 signaling pathways during sepsis. Male and female wild-type (WT), P2Y12 knock-out (KO), and P2Y1 KO mice underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis. The P2Y12 antagonist ticagrelor or the P2Y1 antagonist MRS2279 were administered intra-peritoneally after surgery to septic male and female mice. Blood, lungs and kidneys were collected 24 hours post-surgery. Sepsis-induced changes in platelet activation, secretion and platelet interaction with immune cells were measured by flow cytometry. Neutrophil infiltration in the lung and kidney was determined by a myeloperoxidase (MPO) colorimetric assay kit. Sepsis-induced platelet activation, secretion and aggregate formation were reduced in male CLP P2Y12 KO and in female CLP P2Y1 KO mice compared with their CLP WT counterpart. Sepsis-induced MPO activity was reduced in male CLP P2Y12 KO and CLP P2Y1 KO female mice. CLP males treated with ticagrelor or MRS2279 showed a decrease in sepsis-induced MPO levels in lung and kidneys, aggregate formation, and platelet activation as compared to untreated male CLP mice. There were no differences in platelet activation, aggregate formation, and neutrophil infiltration in lung and kidney between female CLP mice and female CLP mice treated with ticagrelor or MRS2279. In human T lymphocytes, blocking P2Y1 or P2Y12 alters cell growth and secretion in vitro in a sex-dependent manner, supporting the data obtained in mice. In conclusion, targeting purinergic signaling represents a promising therapy for sepsis but drug targeting purinergic signaling is sex-specific and needs to be investigated to determine sex-related targeted therapies in sepsis.

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“…This group of drugs includes: Abciximab, Eptifibatide, and Tirofiban. They are administered intravenously in patients undergoing percutaneous coronary interventions (PCI) and in acute coronary syndromes (ACS) [ 9 , 10 ].…”

Section: Drugs Used In Antiplatelet Therapymentioning

confidence: 99%

Perioperative Management of Dental Surgery Patients Chronically Taking Antithrombotic Medications

Wojcik

Mocny‐Pachońska

Bisch-Wójcik

et al. 2022

IJERPH

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The development of medicine is based not only on the introduction of new methods of treatment, but also on the use of increasingly effective drugs, including antithrombotic drugs. Drugs that inhibit the activity of platelets (antiplatelet and anti-aggregating drugs) and pharmaceuticals that inhibit the activity of plasma coagulation factors (anticoagulants) are used in antithrombotic therapy. In our daily practice we encounter patients who take chronic antiplatelet or anticoagulant drugs. However, more and more often we are dealing with patients who are treated with two antiplatelet drugs, an antiplatelet and an anticoagulant or even undergoing triple antithrombotic therapy. When preparing the patient for invasive craniofacial procedures, it should be assessed whether the temporary discontinuation of antithrombotic treatment due to the fear of excessive perioperative bleeding is justified and will not result in life-threatening thromboembolic complications. The authors discuss in detail the medications used in modern antithrombotic treatment and present a perioperative management procedure with a patient who takes l4 z of these medications chronically.

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Application of Auxiliary VerifyNow Point-of-Care Assays to Assess the Pharmacodynamics of RUC-4, a Novel αIIbβ3 Receptor Antagonist

Cited by 5 publications

References 51 publications

Comparison of the effects of the GPIIb-IIIa antagonist Zalunfiban and the P2Y12 antagonist Selatogrel on Platelet Aggregation

Comparison of the effects of the GPIIb-IIIa antagonist Zalunfiban and the P2Y12 antagonist Selatogrel on Platelet Aggregation

Sex-related differences in the response of anti-platelet drug therapies targeting purinergic signaling pathways in sepsis

Perioperative Management of Dental Surgery Patients Chronically Taking Antithrombotic Medications

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