Effects of different doses of ticagrelor on platelet aggregation and endothelial function in diabetic patients with stable coronary artery disease

We performed this study to observe the effects of different doses of ticagrelor and standard-dose clopidogrel on platelet reactivity and endothelial function in diabetic patients with stable coronary artery disease (CAD). Sixty type 2 diabetic patients were assigned to one-quarter standard-dose ticagrelor, half standard-dose ticagrelor, standard-dose ticagrelor and standard-dose clopidogrel groups. Light transmission aggregometry (LTA) and VerifyNow assay were used to measure platelet function. Endothelial function was assessed by measurement of flow-mediated vasodilation (FMD) and plasma von Willebrand factor (VWF) levels were detected. Enzyme-linked immunosorbent assay (ELISA) examined the Interleukin-8(IL-8) and IL-10. The results suggested that the one-quarter dose (34.0%± 14.7%), half-dose (26.9%± 11.6%) and standard-dose (17.3%± 10.3%) ticagrelor showed lower platelet aggregation rate than clopidogrel (52.8%± 18.3%; P ＜0.0001). PRU values in three ticagrelor groups were lower than that in clopidogrel group (102 (76–184)；75 (33–88)；38 (11–52) versus 194 (138–271) and；P ＜0.0001). FMD levels were higher in ticagrelor groups compared with baseline levels while lower in clopidogrel group after treatment. However, no significant differences were found in the percentage increase in the FMD between ticagrelor groups and clopidogrel group. The levels of VWF after treatment were lower than the baseline levels, but there was no statistically significant difference between ticagrelor group and clopidogrel group after treatment. The concentration of IL-8 and IL-10 were decreased in patients with half and standard-dose ticagrelor group. In conclusion, one-quarter standard-dose ticagrelor produced similar inhibitory effects on platelet aggregation as standard-dose clopidogrel in diabetic patients with stable CAD. The half standard-dose ticagrelor had a similar inhibitory effect on platelet inhibition as standard-dose ticagrelor, which was stronger than that of clopidogrel. Moreover, the half-dose ticagrelor had equal protection of endothelial function and inhibition of inflammatory factor as standard-dose ticagrelor

Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study

Methyl (S)-4-(6-amino-9H-purin-9-yl)-2-hydroxybutanoate (DZ2002) is a potent reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH). Due to its ester structure, DZ2002 is rapidly hydrolyzed in rat blood to 4-(6-amino-9H-purin-9-yl)-2-hydroxybutyric acid (DZA) during and after blood sampling from rats; this hampers accurate determination of the circulating DZ2002 and its acid metabolite DZA in rats. To this end, a method for determining the blood concentrations of DZ2002 and DZA in rats was developed by using methanol to immediately deactivate blood carboxylesterases during sampling. The newly developed bioanalytical assay possessed favorable accuracy and precision with lower limit of quantification of 31 nM for DZ2002 and DZA. This validated assay was applied to a rat pharmacokinetic study of DZ2002. After oral administration, DZ2002 was found to be extensively converted into DZA. The level of systemic exposure to DZ2002 was significantly lower than that of DZA. The apparent oral bioavailability of DZ2002 was 90%–159%. The mean terminal half-lives of DZ2002 and DZA were 0.3–0.9 and 1.3–5.1 h, respectively. The sample preparation method illustrated here may be adopted for determination of other circulating ester drugs and their acid metabolites in rodents. Keywords: S-adenosyl-L-homocysteine hydrolase, DZ2002, Carboxylesterases, Pharmacokinetic

Efficacy and safety of different ticagrelor regimens versus clopidogrel in patients with coronary artery disease: a retrospective multicenter study (SUPERIOR)

Current guidelines favor dual anti-platelet therapy with ticagrelor 90 mg BID (T90BID) over clopidogrel 75 mg QD (C75QD) in addition to aspirin for acute coronary syndrome. However, an increased risk of ticagrelor-related adverse events prompted the evaluation of low-dose regimens. This study (NCT03381742) retrospectively analyzed the data from 11 hospitals on 3,043 patients with coronary artery disease, who received C75QD, T90BID, ticagrelor 45 mg BID (T45BID), or ticagrelor 90 mg QD (T90QD). Compared with C75QD, both T45BID and T90QD showed significantly higher inhibition of platelet aggregation (P < .0001) and lower platelet-fibrin clot strength (P < .0001) induced by adenosine diphosphate. Furthermore, compared with T90BID, two low-dose regimens had a much lower minor bleeding rate and a significantly higher proportion of patients within the therapeutic window for P2Y12 receptor reactivity. There were no significant differences between T45BID and T90QD in the trough plasma concentrations of ticagrelor and its active metabolite. Similar efficacy and safety outcomes were observed in the propensity score-matched analysis. In conclusion, the low-dose ticagrelor regimen, either T45BID or T90QD, may provide a more attractive benefit-risk profile than C75QD or T90BID

Plasma MicroRNAs as Potential Noninvasive Biomarkers for In-Stent Restenosis

<div><p>Objective</p><p>To investigate whether microRNAs (miRs) can serve as novel biomarkers for in-stent restenosis (ISR).</p><p>Methods</p><p>This retrospective, observational single-centre study was conducted at the cardiovascular department of a tertiary hospital centre in the north of China. Follow-up coronary angiography at 6 to 12 months was performed in 181 consecutive patients implanted with drug-eluting stents. Fifty-two healthy volunteers served as the control group. The plasma miRs levels were analyzed by quantitative real-time PCR. Receiver-operating characteristic curve (ROC) analysis was performed to investigate the characters of these miRs as potential biomarkers of ISR.</p><p>Results</p><p>MiR-21 levels in ISR patients were significantly higher than those in non-ISR patients and healthy controls (<i>P</i><0.05), while miR-100 (<i>P</i><0.05), miR-143 (<i>P</i><0.001) and miR-145 (<i>P</i><0.0001) levels were significantly decreased in ISR patients. Further analysis showed that miR-21 levels were remarkably increased (<i>P</i> = 0.045), while miR-100 (<i>P</i> = 0.041), miR-143 (<i>P</i> = 0.029) and miR-145 (<i>P</i><0.01) levels were dramatically decreased in patients with diffuse ISR compared to those with focal ISR. ROC analysis demonstrated that the area under curve of miR-145, miR-143, miR-100 and miR-21 were 0.880 (95% confidence interval; CI = 0.791–0.987, <i>P</i><0.001), 0.818 (95% confidence interval; CI = 0.755–0.963, <i>P</i><0.001), 0.608 (95% confidence interval; CI = 0.372–0.757, <i>P</i><0.05) and 0.568 (95% confidence interval; CI = 0.372–0.757, <i>P</i><0.05), with specificity of 83.1%, 80.1%, 68.9% and 68.6%, and sensitivity of 88.7%, 82.1%, 60.2% and 50.1%, respectively.</p><p>Conclusions</p><p>Circulating miR-143 and miR-145 levels are associated with the occurrence of ISR and can serve as novel noninvasive biomarkers for ISR.</p></div

Representative angiographic images of non-ISR, focal and diffuse ISR.

<p>Angiographic results after successful percutaneous coronary intervention with stent implantation in the left anterior descending coronary artery from three different patients (1A, 2A and 3A). Follow-up angiography showed non-ISR (1B), focal ISR (2B) and diffuse ISR (3B) respectively. White arrows indicate the margins of stent. Black arrows indicate the stenotic lesions.</p

Clinical characteristics of patients between ISR group and non-ISR group used for miRNAs profiling.

<p>Data are presented as means (±SD) or as numbers (percentages).</p><p>*<i>P</i><0.05 vs. Non-ISR.</p><p>Clinical characteristics of patients between ISR group and non-ISR group used for miRNAs profiling.</p

Global view of the network.

<p>Global view of the network.</p