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CYP2C19 genotypes and their impact on clopidogrel responsiveness in percutaneous coronary intervention

Mejin M, Tiong WN, Lai LY, Tiong LL, Bujang AM, Hwang SS, et al.

Int J Clin Pharm, 2013 Aug;35(4):621-8.
PMID: 23661171 DOI: 10.1007/s11096-013-9783-y

BACKGROUND: Cytochrome P450 2C19 (CYP2C19) loss-of-function polymorphisms are more common in Asian populations and have been associated with diminished antiplatelet response to clopidogrel. In this era of 'personalised medicine', combining genotyping and phenotyping as a strategy to personalise antiplatelet therapy warrants further exploration.
OBJECTIVE: This study aimed to investigate the prevalence and impact of CYP2C19*2, *3 and *17 genotypes on clopidogrel responsiveness in a multiethnic Malaysian population planned for percutaneous coronary intervention.
SETTING: Between October 2010 and March 2011, a total of 118 consecutive patients planned for percutaneous coronary intervention were enrolled in Sarawak General Hospital, Borneo. All patients received at least 75 mg aspirin daily for at least 2 days and 75 mg clopidogrel daily for at least 4 days prior to angiography.
METHOD: Genotyping for CYP2C19*2 (rs4244285, 681G > A), *3 (rs4986893, 636G > A) and *17 (rs11188072, -3402C > T) alleles were performed by polymerase chain reaction-restriction fragment linked polymorphism method. Whole blood ADP-induced platelet aggregation was assessed with multiple electrode platelet aggregometry (MEA) using the Multiplate Analyzer.
MAIN OUTCOME MEASURES: The distribution of CYP2C19*2, *3 and *17 among different ethnic groups and the association between genotype, clopidogrel responsiveness and clinical outcome were the main outcome measures.
RESULTS: The highest prevalence of poor metabolisers (carriers of at least one copy of the *2 or *3 allele) was among the Chinese (53.7 %), followed by the Malays (26.9 %), Ibans (16.4 %) and other races (3.0 %). Poor metabolisers (PMs) had the highest mean MEA (303.6 AU*min), followed by normal metabolisers (NMs) with 270.5 AU*min and extensive metabolisers (EMs) with 264.1 AU*min (p = 0.518). Among poor responders to clopidogrel, 65.2 % were PMs and NMs, respectively, whereas none were EMs (p = 0.350). Two cardiac-related deaths were reported.
CONCLUSION: There was a diverse inter-ethnic difference in the distribution of CYP2C19 polymorphism. The findings of this study echo that of other studies where genotype appears to have a limited impact on clopidogrel responsiveness and clinical outcome in low-risk patients.

Matched MeSH terms: Platelet Aggregation/drug effects
Fulltext Platelet-activating factor (PAF) antagonistic activity of a new biflavonoid from Garcinia nervosa var. pubescens King

Jalil J, Jantan I, Ghani AA, Murad S

Molecules, 2012 Sep 10;17(9):10893-901.
PMID: 22964504 DOI: 10.3390/molecules170910893

The methanol extract of the leaves of Garcinia nervosa var. pubescens King, which showed strong inhibitory effects on platelet-activating factor (PAF) receptor binding, was subjected to bioassay-guided isolation to obtain a new biflavonoid, II-3,I-5, II-5,II-7,I-4',II-4'-hexahydroxy-(I-3,II-8)-flavonylflavanonol together with two known flavonoids, 6-methyl-4'-methoxyflavone and acacetin. The structures of the compounds were elucidated by spectroscopic methods. The compounds were evaluated for their ability to inhibit PAF receptor binding to rabbit platelets using ³H-PAF as a ligand. The biflavonoid and acacetin showed strong inhibition with IC₅₀ values of 28.0 and 20.4 µM, respectively. The results suggest that these compounds could be responsible for the strong PAF antagonistic activity of the plant.

Matched MeSH terms: Platelet Aggregation/drug effects
CYP2C19 and PON1 polymorphisms regulating clopidogrel bioactivation in Chinese, Malay and Indian subjects

Chan MY, Tan K, Tan HC, Huan PT, Li B, Phua QH, et al.

Pharmacogenomics, 2012 Apr;13(5):533-42.
PMID: 22462746 DOI: 10.2217/pgs.12.24

AIM, MATERIALS & METHODS: We investigated the functional significance of CYP2C19*2, *3, *17 and PON1 Q192R SNPs in 89 consecutive Asian patients on clopidogrel treatment and the prevalence of functionally significant polymorphisms among 300 Chinese, Malays and Asian Indians.

Matched MeSH terms: Platelet Aggregation/drug effects
Differential expression and geographic variation of the venom phospholipases A2 of Calloselasma rhodostoma and Trimeresurus mucrosquamatus

Tsai IH, Chen YH, Wang YM, Liau MY, Lu PJ

Arch Biochem Biophys, 2001 Mar 15;387(2):257-64.
PMID: 11370849

To investigate the geographic variations in venoms of two medically important pitvipers, we have purified and characterized the phospholipases A2 (PLA2s) from the pooled venoms of Calloselasma rhodostoma from Malaysia, Thailand, Indonesia, and Vietnam, as well as the individual venom of Trimeresurus mucrosquamatus collected from both North and South Taiwan. Enzymatic and pharmacological activities of the purified PLA2s were also investigated. The complete amino acid sequences of the purified PLA2s were determined by sequencing the corresponding cDNAs from the venom gland and shown to be consistent with their molecular weight data and the N-terminal sequences. All the geographic venom samples of C. rhodostoma contain a major noncatalytic basic PLA2-homolog and two or three acidic PLA2s in different proportions. These acidic PLA2s contain Glu6-substitutions and show distinct inhibiting specificities toward the platelets from human and rabbit. We also found that the T. mucrosquamatus venoms from North Taiwan but not those from South Taiwan contain an Arg6-PLA2 designated as TmPL-III. Its amino acid sequence is reported for the first time. This enzyme is structurally almost identical to the low- or nonexpressed Arg6-PLA2 from C. rhodostoma venom gland, and thus appears to be a regressing venom component in both of the Asian pitvipers.

Matched MeSH terms: Platelet Aggregation/drug effects
Isorhapontigenin, a resveratrol analogue selectively inhibits ADP-stimulated platelet activation

Ravishankar D, Albadawi DAI, Chaggar V, Patra PH, Williams HF, Salamah M, et al.

Eur J Pharmacol, 2019 Nov 05;862:172627.
PMID: 31461638 DOI: 10.1016/j.ejphar.2019.172627

Isorhapontigenin is a polyphenolic compound found in Chinese herbs and grapes. It is a methoxylated analogue of a stilbenoid, resveratrol, which is well-known for its various beneficial effects including anti-platelet activity. Isorhapontigenin possesses greater oral bioavailability than resveratrol and has also been identified to possess anti-cancer and anti-inflammatory properties. However, its effects on platelet function have not been reported previously. In this study, we report the effects of isorhapontigenin on the modulation of platelet function. Isorhapontigenin was found to selectively inhibit ADP-induced platelet aggregation with an IC50 of 1.85 μM although it displayed marginal inhibition on platelet aggregation induced by other platelet agonists at 100 μM. However, resveratrol exhibited weaker inhibition on ADP-induced platelet aggregation (IC50 > 100 μM) but inhibited collagen induced platelet aggregation at 50 μM and 100 μM. Isorhapontigenin also inhibited integrin αIIbβ3 mediated inside-out and outside-in signalling and dense granule secretion in ADP-induced platelet activation but interestingly, no effect was observed on α-granule secretion. Isorhapontigenin did not exert any cytotoxicity on platelets at the concentrations of up to 100 μM. Furthermore, it did not affect haemostasis in mice at the IC50 concentration (1.85 μM). In addition, the mechanistic studies demonstrated that isorhapontigenin increased cAMP levels and VASP phosphorylation at Ser157 and decreased Akt phosphorylation. This suggests that isorhapontigenin may interfere with cAMP and PI3K signalling pathways that are associated with the P2Y12 receptor. Molecular docking studies emphasised that isorhapontigenin has greater binding affinity to P2Y12 receptor than resveratrol. Our results demonstrate that isorhapontigenin has selective inhibitory effects on ADP-stimulated platelet activation possibly via P2Y12 receptor.

Matched MeSH terms: Platelet Aggregation/drug effects*
An investigation of the antiplatelet effects of succinobucol (AGI-1067)

Houston SA, Ugusman A, Gnanadesikan S, Kennedy S

Platelets, 2017 May;28(3):295-300.
PMID: 27681689 DOI: 10.1080/09537104.2016.1218456

Succinobucol is a phenolic antioxidant with anti-inflammatory and antiplatelet effects. Given the importance of oxidant stress in modulating platelet-platelet and platelet-vessel wall interactions, the aim of this study was to establish if antioxidant activity was responsible for the antiplatelet activity of succinobucol. Platelet aggregation in response to collagen and adenosine diphosphate (ADP) was studied in rabbit whole blood and platelet-rich plasma using impedance aggregometry. The effect of oxidant stress on aggregation, platelet lipid peroxides, and vascular tone was studied by incubating platelets, washed platelets or preconstricted rabbit iliac artery rings respectively with a combination of xanthine and xanthine oxidase (X/XO). To study the effect of succinobucol in vivo, anaesthetized rats were injected with up to 150 mg/kg succinobucol and aggregation measured in blood removed 15 mins later. Succinobucol (10-5-10-4M) significantly attenuated platelet aggregation to collagen and ADP in whole blood and platelet-rich plasma. X/XO significantly increased aggregation to collagen and platelet lipid peroxides and this was reversed by succinobucol. Addition of X/XO to denuded rabbit iliac arteries caused a dose-dependent relaxation which was significantly inhibited by succinobucol. In vivo administration up to 150 mg/kg had no effect on heart rate or mean arterial blood pressure but significantly inhibited platelet aggregation to collagen ex vivo. In conclusion, succinobucol displays anti-platelet activity in rabbit and rat blood and reverses the increase in platelet aggregation in response to oxidant stress.

Matched MeSH terms: Platelet Aggregation/drug effects*
Inhibitory effect of compounds from Goniothalamus tapis Miq. and Goniothalamus uvaroides King on platelet-activating factor receptor binding

Moharam BA, Jantan I, Jalil J, Ahmad F

Phytother Res, 2012 May;26(5):687-91.
PMID: 22002630 DOI: 10.1002/ptr.3620

Phytochemical investigation on the bark of Goniothalamus tapis Miq. and G. uvaroides King has resulted in the isolation of eight styryl-lactones, (-)-cryptomeridiol, liriodenine, 3-methyl-1H-benz[f]indole-4,9-dione, (-)-stigmasterol and dimethyl terephthalate. The structures of the compounds were elucidated by spectroscopic techniques. The compounds were evaluated for their effect on platelet-activating factor (PAF) receptor binding on rabbit platelets using (3) H-PAF as a ligand. Among the compounds tested, (-)-cryptomeridiol, (+)-goniothalamin and (+)-isoaltholactone exhibited a significant and concentration-dependent inhibitory effect on PAF receptor binding, with inhibitory concentration (IC)(50) values of 17.5, 19.7 and 46.5 µm, respectively. The inhibitory effects of the first two compounds were comparable to that obtained from the positive control, cedrol. The results indicated that these compounds were strong PAF receptor binding inhibitors.

Matched MeSH terms: Platelet Aggregation/drug effects