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  1. 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/pharmacology*
  2. 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*
  3. 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*
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