- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: Osteoblasts Promote Prostate Cancer Cell Proliferation Through Androgen Receptor Independent Mechanisms. (Pubmed Central) - Jan 1, 2022
Although the increase of C4-2B cell growth induced by MMP-1 did not reach the proliferation levels observed after OCM treatment, the addition of Vorapaxar, an MMP-1 receptor inhibitor (Protease-activated receptor-1, PAR-1), significantly reduced C4-2B cell cycle (0.1 μM p = 0.014; 1 μM p = 0.0087). Overall, our results provide a novel AR-independent mechanism of CRPC proliferation and suggest that MMP-1/PAR-1 could be one of the potential pathways involved in this process.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Clinical, Journal: PAR-1 Antagonism to Promote Gut Mucosa Healing in Crohn's Disease Patients: A New Avenue for CVT120165. (Pubmed Central) - Dec 16, 2021
The potential clinical benefits of PAR-1 antagonism to promote mucosal repair in CD patients are discussed. Targeted local delivery of a PAR-1 antagonist molecule such as CVT120165, a formulated version of the FDA-approved PAR-1 antagonist vorapaxar, at the mucosa of Crohn's disease patients could be proposed as a new indication for IBD that could be rapidly tested in clinical trials.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Review, Journal: Protease-Activated Receptor Antagonist for Reducing Cardiovascular Events - A Review on Vorapaxar. (Pubmed Central) - Nov 2, 2021
Based upon further subgroup analysis of both the TRA 2°P-TIMI 50 trial and TRACER trial, Vorapaxar was found to be potentially beneficial in patients with peripheral artery disease, coronary artery bypass grafting, and ischemic stroke. There are current trials in progress that are further evaluating the use of Vorapaxar in those conditions, and future research and trials are necessary to fully determine the utility of this drug.
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Journal: Vorapaxar in the treatment of cardiovascular diseases. (Pubmed Central) - Oct 27, 2021
Based on these favorable results, vorapaxar was approved for the reduction of thrombotic cardiovascular events in patients with prior myocardial infarction or with peripheral artery disease on top of standard antiplatelet therapy. A careful patient selection is needed to balance efficacy versus safety.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury. (Pubmed Central) - Oct 22, 2021
Our results demonstrate that SCH530348 exerts protective effects by blocking PAR-1 expression and modulating the downstream PI3K, NF-κB and MAPK pathways. These findings indicate that the PAR-1 antagonist protects against IR-induced ALI and is a potential therapeutic candidate for lung protection following IR injury.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal, Benefit-risk assessment: Benefit-Risk Tradeoffs in Assessment of New Drugs and Devices. (Pubmed Central) - Oct 1, 2021
We give illustrative examples of benefit-risk evaluations using 4 treatment interventions including sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes; a direct antithrombin agent, dabigatran, for reducing stroke and systemic embolism in patients with nonvalvular atrial fibrillation; transcatheter aortic valve replacement in patients with symptomatic severe aortic valve stenosis; and antiplatelet agents vorapaxar and prasugrel for reducing cardiovascular events in patients at high cardiovascular risk. Regular applications of structured benefit-risk assessment, whether qualitative, quantitative, or both, enabled by easy-to-understand graphical presentations that capture uncertainties around the benefit-risk metric, may aid shared decision-making and enhance transparency of those decisions.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Preclinical, Journal: Novel positive allosteric modulator of protease-activated receptor 1 promotes skin wound healing in hairless mice. (Pubmed Central) - Sep 23, 2021
Regular applications of structured benefit-risk assessment, whether qualitative, quantitative, or both, enabled by easy-to-understand graphical presentations that capture uncertainties around the benefit-risk metric, may aid shared decision-making and enhance transparency of those decisions. Our results revealed that GB83 is the first positive allosteric modulator of PAR1, and it can be a useful pharmacological tool for studying PAR1 and a potential therapeutic agent for skin wound healing.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: Enantioselective synthesis of a chiral intermediate of himbacine analogs by Burkholderia cepacia lipase A. (Pubmed Central) - Jul 29, 2021
The enantiomers of (4R/S)-4-hydroxy-N, N-diphenyl-2-pentynamide are key chiral synthons for the synthesis of thrombin receptor antagonists such as vorapaxar...Using the optimize conditions, (4R)-4-hydroxy-N, N-diphenyl-2-pentynamide with 94.5% ee value and 48.93% conversion ratio was achieved. Our investigation on this lipase reveals lipase A as a promising biocatalyst for producing chiral propargyl alcohol for preparation of novel himbacine analogs.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: Misreported Cancer Deaths in PLATO Trial. (Pubmed Central) - Jul 27, 2021
We conclude that some CD were misreported in PLATO, favoring ticagrelor. Such mismatch may require reevaluation of this critical outcome in the trial focusing on the exact death cause reported by site investigators.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: Sarsasapogenin ameliorates diabetes-associated memory impairment and neuroinflammation through down-regulation of PAR-1 receptor. (Pubmed Central) - Jun 30, 2021
Moreover, the effects of Sar were similar to those of a selective PAR-1 antagonist vorapaxar...Further studies indicated that activation of the NLRP1 inflammasome and NF-κB mediated the effect of PAR-1 up-regulation in high glucose condition by using PAR-1 knockdown assay. In summary, this study demonstrated that Sar prevented memory impairment caused by diabetes, which was achieved through suppressing neuroinflammation from activated NLRP1 inflammasome and NF-κB regulated by cerebral PAR-1.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Review, Journal: Pathogenesis and management of heparin-induced thrombocytopenia and thrombosis. (Pubmed Central) - Jun 22, 2021
Thirdly, two activation signals of platelets (protease-activated receptor 1/ Fc gamma IIA receptor) were confirmed. Based on these findings, we present a potential laboratory test of HITT (receptor glycoprotein Ⅳ) and two possible treatments by using receptor inhibitors (vorapaxar/atopaxar) and IgG-degrading enzyme (streptococcus pyogenes/glutamyl endopeptidase V8/ matrix metalloproteinases).
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Journal: Ca mobilization and signaling pathways induced by rRgpB in human gingival fibroblast. (Pubmed Central) - Jun 22, 2021
rRgpB caused a transient increase in [Ca], which could be completely suppressed by vorapaxar, a PAR-1 antagonist...: rRgpB causes an increase in [Ca] in HGF mediated by PAR-1. JNK, ERK1/2 and nuclear factor-κB may be involved in intracellular signal transduction after PAR-1 activation.
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[VIRTUAL] Study of the Affinity of Thrombin towards its Receptors on Platelets (Room 3) - Jun 9, 2021 - Abstract #ISTH2021ISTH_1420;
Conclusions : The affinity of thrombin towards its receptors on platelets is in the order of PAR1>PAR4>GP1b. MST is a useful and non-harmful technique that can be used to study the interaction of biomolecules with platelets.
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Journal: Vorapaxar-modified polysulfone membrane with high hemocompatibility inhibits thrombosis. (Pubmed Central) - May 15, 2021
To determine the biosafety of VMPSf membranes, we investigated antianaphylactic and anti-inflammatory properties in vitro and acute toxicity in vivo, it was obvious that C3a and C5a had decreased to 9.6 and 0.8 ng/mL, respectively. The results indicated that the VMPSf membrane has potential for clinical application.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: Design and synthesis of potent PAR-1 antagonists based on vorapaxar. (Pubmed Central) - May 1, 2021
Among these analogues, 3d exhibited excellent PAR-1 inhibitory activity (IC = 0.18 μM) and the lower ability to cross the blood-brain barrier compared with vorapaxar (IC = 0.25 μM). Compound 3d has the potential to be developed as a new generation of PAR-1 antagonists with a better therapeutic window.
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Clinical, Journal, Real-world evidence: Mortality benefit with different antithrombotic therapies in patients with stable vascular disease: from pathophysiology to the clinical impact in the real world. The COMPASS study (Pubmed Central) - Apr 29, 2021
Such mortality benefit was not observed in previous randomized trials that in this setting of patients had previously evaluated antiplatelet strategies alternative to aspirin (with clopidogrel) or had compared a dual antiplatelet therapy with aspirin plus clopidogrel, vorapaxar, or ticagrelor vs a single antiplatelet treatment with aspirin. The results of the COMPASS trial strengthen the role of antithrombotic strategies that, beside the platelet phase, also involve the coagulative phase with the aim at preventing the recurrence of cardiovascular, atherothrombotic events at the site of polyvascular beds, with a degree of benefit proportional to the baseline risk of the patient.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: Cholesterol-Rich Microdomains Contribute to PAR1 Signaling in Platelets Despite a Weak Localization of the Receptor in These Microdomains. (Pubmed Central) - Mar 30, 2021
Targeting the PAR1 pathway by vorapaxar, a PAR1 antagonist, leads to a reduction in ischemic events in cardiovascular patients with a history of myocardial infarction or with peripheral arterial disease...Consistent with a cholesterol-dependent activation of Akt and p38 MAP kinase in thrombin receptor-activating peptide (TRAP)-activated platelets, the proteomic data of cholesterol-rich microdomains isolated from TRAP-activated platelets showed the recruitment of proteins contributing to these signaling pathways. In conclusion, contrary to endothelial cells, we found that PAR1 was only weakly present in cholesterol-rich microdomains in human platelets but used these microdomains for efficient activation of downstream signaling pathways following TRAP activation.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: PAR2 Activation on Human Kidney Tubular Epithelial Cells Induces Tissue Factor Synthesis, That Enhances Blood Clotting. (Pubmed Central) - Mar 30, 2021
Thrombin-induced TF was also inhibited by a PAR1 antagonist, Vorapaxar...Thrombin-induced TF synthesis is at least partly mediated by PAR1 transactivation of PAR2. These findings reveal how underlying hemostatic imbalances might increase thrombosis risk and subsequent chronic fibrin deposition in the kidneys of patients with CKD and suggest PAR2 antagonism as a potential therapeutic strategy for intervening in CKD progression.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease. (Pubmed Central) - Feb 3, 2021
Beyond defining a critical role for KLK6-PAR1 signaling in promoting psoriasis, our results demonstrate that KLK6-PAR1-mediated inflammation in the skin alone is sufficient to drive inflammatory joint disease. Further, we identify PAR1 as a promising cytokine-independent target in therapy of psoriasis and psoriatic arthritis.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: Proteinase-activated receptor 1 (PAR1): A target for repurposing in the treatment of COVID-19? (Pubmed Central) - Oct 30, 2020
Vorapaxar is an approved inhibitor of PAR1, used for treatment of patients with myocardial infarction or peripheral arterial disease...Vorapaxar is an approved inhibitor of PAR1, used for treatment of patients with myocardial infarction or peripheral arterial disease. Here, we discuss evidence implying a possible beneficial role for vorapaxar in the treatment of COVID-19 patients and in addition, other as-yet non-approved antagonists of PAR1 and PAR4.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: Platelet Protease Activated Receptor 1 Is Involved in the Hemostatic Effect of 20(S)-Protopanaxadiol by Regulating Calcium Signaling. (Pubmed Central) - Oct 15, 2020
In addition, molecular docking analysis and ELISA assay demonstrated that PPD had a promising docking score with -6.6 kcal/mol and increased PAR-1 expression in human platelets, which indicated that PAR-1 is involved in PPD-induced platelet aggregation by regulating calcium signaling. Collectively, our study could provide the new insights of PPD as an essential hemostatic ingredient in Panax notoginseng for the treatment of hemorrhagic disease.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: Novel Antiplatelet Agents in Cardiovascular Disease. (Pubmed Central) - Oct 8, 2020
As a consequence, many new antiplatelet agents with high antithrombotic efficacy and supposedly only moderate effects on regular hemostasis have been developed and yielded promising results in preclinical and early clinical studies. Although their long journey from animal studies to randomized clinical trials and finally administration in daily clinical routine has just begun, some of the new agents may in the future become meaningful additions to the pharmacological armamentarium in cardiovascular disease.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Preclinical, Journal: Novel Mouse Model for Studying Hemostatic Function of Human Platelets. (Pubmed Central) - Oct 7, 2020
Although their long journey from animal studies to randomized clinical trials and finally administration in daily clinical routine has just begun, some of the new agents may in the future become meaningful additions to the pharmacological armamentarium in cardiovascular disease. We propose that this novel mouse model will provide a robust platform to test and predict the safety and efficacy of experimental antiplatelet drugs and to characterize the hemostatic function of synthetic, stored and patient platelets.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Journal: Pharmacological PAR-1 inhibition reduces blood glucose levels but does not improve kidney function in experimental type 2 diabetic nephropathy. (Pubmed Central) - Jun 4, 2020
Overall, we thus show that PAR-1 inhibition reduces blood glucose levels during the progression of diabetic nephropathy in experimental type 2 diabetes but does not improve renal function. This is in contrast to the therapeutic potential of vorapaxar in type 1 diabetes-induced nephropathy, highlighting the importance of disease-dependent treatment modalities.-Waasdorp, M., Florquin, S., Duitman, J., Spek, C. A. Pharmacological PAR-1 inhibition reduces blood glucose levels but does not improve kidney function in experimental type 2 diabetic nephropathy.
- |||||||||| Brilinta (ticagrelor) / AstraZeneca, aspirin / Generic mfg., Zontivity (vorapaxar) / Merck (MSD)
[VIRTUAL] Novel Mouse Model for Studying Hemostatic Function of Human Platelets (Virtual Meeting Room 6) - May 14, 2020 - Abstract #ISTH2020ISTH_164;
Studies on the anti-hemostatic effect of PAR1-inhibition in the absence and presence of DAPT validate our humanized platelet mouse model as a robust platform to test and predict the safety and efficacy of experimental antiplatelet drugs. We propose that this model will also be of great value for the characterization of in vivo hemostatic/thrombotic potential of synthetic platelets, stored platelets or platelets from patients with a platelet function disorder.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD)
Review, Clinical Trial,Phase I, Clinical Trial,Phase II, Journal: Using PAR4 Inhibition as an Anti-Thrombotic Approach: Why, How, and When? (Pubmed Central) - Apr 1, 2020
However, there are two PARs on human platelets, PAR1 and PAR4, and more recent efforts have focused on the development of the first PAR4 antagonists, with first-in-class agents recently beginning clinical trial. Here, we review the rationale for this approach, outline the various modes of PAR4 inhibition, and speculate on the specific therapeutic potential of targeting PAR4 for the prevention of thrombotic conditions.
- |||||||||| [VIRTUAL] A PAN-EUROPEAN HTA, A SINGLE US PAYER? () - Mar 8, 2020 - Abstract #ISPOR2020ISPOR_1468;
Despite political pressure at the European level there seems little appetite to harmonize HTA nationally. The lack of historical HTA across the US payer landscape is one less hurdle for proponents of a single payer system in the US.
- |||||||||| Zontivity (vorapaxar) / Merck (MSD), PD98059 / Wayne State University
Preclinical, Journal: Antiapoptotic Effect by PAR-1 Antagonist Protects Mouse Liver Against Ischemia-Reperfusion Injury. (Pubmed Central) - Feb 28, 2020
The results of the present study revealed that hepatic IRI induces significant enhancement of PAR-1 expression on SECs, which may be associated with suppression of survival signaling pathways such as ERK 1/2, resulting in severe apoptosis-induced hepatic damage. Thus, the selective PAR-1 antagonist attenuates hepatic IRI through an antiapoptotic effect by the activation of survival-signaling pathways.
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