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P2Y12 antagonists: Approved drugs, potential naturally isolated and synthesised compounds, and related in-silico studies

Al-Najjar BO, Saqallah FG, Abbas MA, Al-Hijazeen SZ, Sibai OA

Eur J Med Chem, 2022 Jan 05;227:113924.
PMID: 34731765 DOI: 10.1016/j.ejmech.2021.113924

P2Y12 is a platelet surface protein which is responsible for the amplification of P2Y1 response. It plays a crucial role in platelet aggregation and thrombus formation through an ADP-induced platelet activation mechanism. Despite that P2Y12 platelets' receptor is an excellent target for developing antiplatelet agents, only five approved medications are currently in clinical use which are classified into thienopyridines and nucleoside-nucleotide derivatives. In the past years, many attempts for developing new candidates as P2Y12 inhibitors have been made. This review highlights the importance and the role of P2Y12 receptor as part of the coagulation cascade, its reported congenital defects, and the type of assays which are used to verify and measure its activity. Furthermore, an overview is given of the clinically approved medications, the potential naturally isolated inhibitors, and the synthesised candidates which were tested either in-vitro, in-vivo and/or clinically. Finally, we outline the in-silico attempts which were carried out using virtual screening, molecular docking and dynamics simulations in efforts of designing novel P2Y12 antagonists. Various phytochemical classes might be considered as a corner stone for the discovery of novel P2Y12 inhibitors, whereas a wide range of ring systems can be deliberated as leading scaffolds in that area synthetically and theoretically.

Matched MeSH terms: Purinergic P2Y Receptor Antagonists/isolation & purification; Purinergic P2Y Receptor Antagonists/pharmacology*; Purinergic P2Y Receptor Antagonists/chemistry
[2021 Asian Pacific Society of Cardiology Consensus Recommendations on the use of P2Y12 receptor antagonists in the Asia-Pacific Region: Special populations]

Tan WEICHIEHTAN, Chew PCHEW, Tsui LAMTSUI, Tan TAN, Duplyakov DUPLYAKOV, Hammoudeh HAMMOUDEH, et al.

Zhonghua Xin Xue Guan Bing Za Zhi, 2023 Jan 24;51(1):19-31.
PMID: 36655238 DOI: 10.3760/cma.j.cn112148-20220729-00588
Matched MeSH terms: Purinergic P2Y Receptor Antagonists
Prasugrel over ticagrelor in non-ST-elevation acute coronary syndromes: is it justified?

Kow CS, Zaihan AF, Hasan SS

Eur Heart J, 2021 07 08;42(26):2609-2610.
PMID: 33205147 DOI: 10.1093/eurheartj/ehaa880
Matched MeSH terms: Purinergic P2Y Receptor Antagonists
2020 Asian Pacific Society of Cardiology Consensus Recommendations on the Use of P2Y12 Receptor Antagonists in the Asia-Pacific Region

Tan JW, Chew DP, Abdul Kader MAS, Ako J, Bahl VK, Chan M, et al.

Eur Cardiol, 2021 Feb;16:e02.
PMID: 33708263 DOI: 10.15420/ecr.2020.40

The unique characteristics of patients with acute coronary syndrome in the Asia-Pacific region mean that international guidelines on the use of dual antiplatelet therapy (DAPT) cannot be routinely applied to these populations. Newer generation P2Y12 inhibitors (i.e. ticagrelor and prasugrel) have demonstrated improved clinical outcomes compared with clopidogrel. However, low numbers of Asian patients participated in pivotal studies and few regional studies comparing DAPTs have been conducted. This article aims to summarise current evidence on the use of newer generation P2Y12 inhibitors in Asian patients with acute coronary syndrome and provide recommendations to assist clinicians, especially cardiologists, in selecting a DAPT regimen. Guidance is provided on the management of ischaemic and bleeding risks, including duration of therapy, switching strategies and the management of patients with ST-elevation and non-ST-elevation MI or those requiring surgery. In particular, the need for an individualised DAPT regimen and considerations relating to switching, de-escalating, stopping or continuing DAPT beyond 12 months are discussed.

Matched MeSH terms: Purinergic P2Y Receptor Antagonists
A review of the effects of ticagrelor on adenosine concentration and its clinical significance

Akkaif MA, Ng ML, Sk Abdul Kader MA, Daud NAA, Sha'aban A, Ibrahim B

Pharmacol Rep, 2021 Dec;73(6):1551-1564.
PMID: 34283374 DOI: 10.1007/s43440-021-00309-0

BACKGROUND: Ticagrelor is an oral antiplatelet drug that can reversibly bind to the platelet P2Y12 receptor. Ticagrelor is metabolized mainly by CYP3A4 and produces a rapid blood concentration-dependent platelet inhibitory effect. Unlike other P2Y12 receptor antagonists, many clinical features of ticagrelor are not related to P2Y12 receptor antagonism.
PURPOSE: This review aims to gather existing literature on the clinical effects of ticagrelor after inhibiting adenosine uptake.
METHODOLOGY: The current study reviewed literature related to the effects of ticagrelor on adenosine metabolism. The review also examined the drug's biological effects and clinical characteristics to see how it could be used in a clinical setting.
RESULTS: Many studies have shown that ticagrelor can inhibit equilibrative nucleoside transporter 1 (ENT1). This inhibition leads to intracellular adenosine uptake, increased adenosine half-life and plasma concentration levels and an enhanced adenosine-mediated biological effect.
CONCLUSIONS: Based on the studies reviewed, it was found that ticagrelor essentially inhibits adenosine absorption of adenosine into cells through ENT1, which increases the concentration in the blood and subsequently increases the protection of the heart muscle by adenosine. It also prevents platelet aggregation, and extends the biological effects of coronary arteries. Moreover, it leads to a lower mortality rate in acute coronary syndrome (ACS) patients.

Matched MeSH terms: Purinergic P2Y Receptor Antagonists/pharmacology*
Fulltext The Role of Genetic Polymorphism and Other Factors on Clopidogrel Resistance (CR) in an Asian Population with Coronary Heart Disease (CHD)

Akkaif MA, Daud NAA, Sha'aban A, Ng ML, Abdul Kader MAS, Noor DAM, et al.

Molecules, 2021 Apr 01;26(7).
PMID: 33915807 DOI: 10.3390/molecules26071987

Clopidogrel is a widely-used antiplatelet drug. It is important for the treatment and prevention of coronary heart disease. Clopidogrel can effectively reduce platelet activity and therefore reduce stent thrombosis. However, some patients still have ischemic events despite taking the clopidogrel due to the alteration in clopidogrel metabolism attributable to various genetic and non-genetic factors. This review aims to summarise the mechanisms and causes of clopidogrel resistance (CR) and potential strategies to overcome it. This review summarised the possible effects of genetic polymorphism on CR among the Asian population, especially CYP2C19 *2 / *3 / *17, where the prevalence rate among Asians was 23.00%, 4.61%, 15.18%, respectively. The review also studied the effects of other factors and appropriate strategies used to overcome CR. Generally, CR among the Asian population was estimated at 17.2-81.6%. Therefore, our overview provides valuable insight into the causes of RC. In conclusion, understanding the prevalence of drug metabolism-related genetic polymorphism, especially CYP2C19 alleles, will enhance clinical understanding of racial differences in drug reactions, contributing to the development of personalised medicine in Asia.

Matched MeSH terms: Purinergic P2Y Receptor Antagonists/pharmacology*; Purinergic P2Y Receptor Antagonists/therapeutic use
Fulltext Trends in evidence-based treatment and mortality for ST elevation myocardial infarction in Malaysia from 2006 to 2013: time for real change

Venkatason P, Zubairi YZ, Hafidz I, Wan WA, Zuhdi AS

Ann Saudi Med, 2016 5 30;36(3):184-9.
PMID: 27236389 DOI: 10.5144/0256-4947.2016.184

BACKGROUND: The administration of evidence-based pharmacotherapy and timely primary percutaneous coronary intervention have been shown to improve outcome in ST elevation myocardial infarction (STEMI). However, implementation remains a challenge due to the limitations in facilities, expertise and funding.
OBJECTIVES: To investigate adherence to guideline-based management and mortality of STEMI patients in Malaysia.
DESIGN: Retrospective analysis.
SETTINGS: STEMI patients from 18 participating hospital across Malaysia included in the National Cardiovascular Database-Acute Coronary Syndrome (NCVD-ACS) registry year 2006 to 2013.
PATIENTS AND METHODS: Patients were categorized into four subgroups based on the year of admission (2006 to 2007, 2008 to 2009, 2010 to 2011 and 2012 to 2013). Baseline characteristics and clinical presentation, in-hospital pharmacotherapy, invasive revascularization and in-hospital/30-day mortality were analysed and compared between the subgroups.
MAIN OUTCOME MEASURE(S): Rate of in-hospital catheterization/percutaneous coronary intervention.
RESULTS: The registry contained data on 19483 patients. Intravenous thrombolysis was the main reperfusion therapy. Although the overall rate of in-hospital catheterisation/PCI more than doubled over the study period, while the use of primary PCI only slowly increased from 7.6% in 2006/2007 to 13.6% in 2012/2013. The use of evidence-based oral therapies increased steadily over the years except for ACe-inhibitors and angiotensin-receptor blockers. The adjusted risk ratios (RR) for in-hospital mortality for the four sub-groups have not shown any significant improvement. The 30-day adjusted risk ratios however showed a significant albeit gradual risk reduction (RR 0.773 95% CI 0.679-0.881, P < .001).
CONCLUSION: Adherence to evidence-based treatment in STEMI in Malaysia is still poor especially in terms of the rate of primary PCI. Although there is a general trend toward reduced 30-day mortality, the reduction was only slight over the study period. Drastic effort is needed to improve adherence and clinical outcomes.
LIMITATION: Retrospective registry data with inter-hospital variation.

Matched MeSH terms: Purinergic P2Y Receptor Antagonists/therapeutic use