Pharmacodynamic effects of indobufen compared with aspirin in patients with coronary atherosclerosis.

PURPOSE: This study aimed to investigate the pharmacodynamic effects of indobufen and low-dose aspirin in patients with coronary atherosclerosis. METHODS: In the first phase, 218 patients with coronary atherosclerosis were randomly assigned to receive aspirin 100 mg once daily (standard dose); 100 mg once every 2 days; 100 mg once every 3 days; 50 mg twice daily; 75 mg once daily; 50 mg once daily; or indobufen 100 mg twice daily for 1 month. In the second phase, 20 healthy subjects were treated with indobufen 100 mg twice daily for 1 week followed after a 2-week washout by aspirin 100 mg once daily for 1 week. The primary outcome was arachidonic acid-induced platelet aggregation (PLAA), and the secondary outcomes included plasma thromboxane B2 (TXB2) and urinary 11-dehydro-TXB2 (11-dh-TXB2) levels at the end of each treatment.  RESULTS: In the first phase, compared with aspirin 100 mg once daily: all aspirin groups had similar suppression of PLAA whereas indobufen group had significantly less suppressed PLAA. Aspirin given every second or third day, and indobufen produced less suppression of plasma TXB2. All treatment regimens produced similar inhibition of 11-dh-TXB2. In the second phase, compared with aspirin, indobufen produced less suppression of plasma TXB2 at 8 h and 12 h after the last dose. CONCLUSIONS: Aspirin 50 mg twice daily, 75 mg once daily, and aspirin 50 mg once daily produce antiplatelet effects that are similar to aspirin 100 mg once daily. Aspirin given less often than once daily and indobufen 100 mg twice daily do not suppress platelets as effectively as aspirin 100 mg once daily.

Cyclic RGD functionalized liposomes targeted to activated platelets for thrombosis dual-mode magnetic resonance imaging.

Thrombotic disease is a serious threat to human health. The rapid and accurate detection of thrombosis is still a clinical challenge. To achieve the accurate diagnosis of thrombosis with magnetic resonance imaging (MRI), nanomaterials-based contrast agents have been developed in recent years. In this study, cyclic RGD functionalized liposomes targeted to the activated platelets are developed for thrombosis dual-mode MRI. The cyclic RGD functionalized liposomes (cRGD@MLP-Gd) encapsulated with gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA) and superparamagnetic iron oxide (SPIO) are prepared, and their thrombus-targeted T1 and T2 MRI potential is evaluated in vitro and in vivo. Results show that cRGD@MLP-Gd could actively bind to the activated platelets and gradually accumulate at the thrombus site with a T1 - T2 contrast enhancement imaging effect in vitro. In in vivo MRI experiments, cRGD@MLP-Gd exhibits a T2 contrast enhancement at 1 h after intravenous administration, followed by a visibly larger T1 contrast enhancement at the thrombus site. This dynamic property showed that cRGD@MLP-Gd could actively bind to thrombus and possessed an enhanced T1 and T2 dual-mode MRI effect in vivo. Our results establish the characterization, feasibility and superiority of cRGD@MLP-Gd for the rapid identification of thrombosis, showing great potential to improve diagnostic accuracy and sensitivity to thrombosis of the MRI technique.

Vildagliptin Reduces Stenosis of Injured Carotid Artery in Diabetic Mouse Through Inhibiting Vascular Smooth Muscle Cell Proliferation via ER Stress/NF-κB Pathway.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel anti-hyperglycemic drugs for type 2 diabetes. It has been reported that DDP-4 inhibitor could exert pleiotropic effects on cardiovascular system. This study was to explore the effect and mechanism of vildagliptin on the stenosis of injured carotid artery in diabetic mouse. Twenty six-week-old male db/db mice (BKS) were randomized into vildagliptin treated and vehicle control groups. Ligation injury was first performed in left carotid arteries of all diabetic mice, then oral vildagliptin or equal amount of PBS was correspondingly administered to the mice from the next day to ligation injury for 4 weeks. Effects on proliferation were detected via histological and morphometric analysis. Endoplasmic reticulum (ER) stress and nuclear factor kappa B (NF-κB) markers were determined by immunoblot analysis. After 4 weeks of vildagliptin delivery, it was observed that the intimal area and neointimal thickness of the ligated carotid arteries were significantly reduced as compared to the control group. In vivo, vildagliptin suppressed the expressions of PCNA and α-SMA, phospho-p65, phospho-IKKα/ß, GRP78 and CHOP, as well as IRE-1 in vascular smooth muscle cells (VSMCs). In vitro, the proliferation and hypertrophy of VSMCs were significantly inhibited by blocking the IRE-1 pathway, and the inhibition of phospho-IRE-1 expression down-regulated the expression of phospho-IKKα/ß in VSMCs. Vildagliptin reduced the stenosis of injured carotid arteries in diabetic mice, and this effect was achieved via inhibiting the activation of ER stress/NF-κB pathway.

Reversal of the antiplatelet effect of ticagrelor by simulated platelet transfusion.

BACKGROUND: Reversal of antiplatelet therapy is desirable in patients presenting with life-threatening bleeding or requiring urgent surgery. This study aimed to examine ticagrelor reversal using donor platelets and to explore the effects of residual ticagrelor on donor platelets. STUDY DESIGN AND METHODS: In Cohort 1, 16 healthy subjects were treated with ticagrelor 90 mg twice daily alone or in combination with aspirin 100 mg once daily for 7 days followed by single blood sampling for preparation of platelet-rich plasma. An additional 16 healthy subjects served as controls. In Cohort 2, 16 healthy subjects were treated with ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 7 days followed by serial blood samplings for preparation of platelet-poor plasma (PPP). An additional 16 healthy subjects served as controls. RESULTS: In Cohort 1, inhibition of adenosine diphosphate-induced platelet aggregation (PLADP ) by ticagrelor could not be fully reversed by mixing with up to 90% control platelets, whereas inhibition of arachidonic acid-induced platelet aggregation by aspirin was fully reversed with the addition of 60% control platelets. In Cohort 2, 10% PPP obtained from ticagrelor-treated subjects reduced PLADP from 74% to 40% at 2 hours, 72% to 58% at 6 hours, and 73% to 59% at 10 hours, while 10% or 20% PPP obtained from clopidogrel-treated subjects did not inhibit PLADP . CONCLUSION: The antiplatelet effect of ticagrelor cannot be fully reversed by donor platelets, which could be explained by the presence of active drug. The effect of residual drug on donor platelets appears to be evident for at least 10 hours after ticagrelor ingestion.

The Value of Pre-Infarction Angina and Plasma D-Dimer in Predicting No-Reflow After Primary Percutaneous Coronary Intervention in ST-Segment Elevation Acute Myocardial Infarction Patients.

BACKGROUND Primary percutaneous coronary intervention (PCI) has improved outcomes greatly in patients with ST-elevation myocardial acute infarction (STEMI). However, the no-reflow phenomenon significantly reduces its efficacy. MATERIAL AND METHODS In this study, we investigated the value of combining plasma D-dimer level on admission and pre-infarction angina (PIA) in predicting no-reflow phenomenon in STEMI patients after primary PCI. A total of 926 STEMI patients who underwent primary PCI were included. RESULTS The average age was 52.6 years, 617 (66.6%) of them had experienced a PIA, and 435 (47.9%) showed no-reflow phenomenon after primary PCI. Both PIA and plasma D-dimer on admission were independent predictors of no-reflow, with a risk of 0.516 (95% CI: 0.380 to 0.701) and 2.563 (95% CI: 1.910 to 3.439), respectively. Plasma D-dimer level had an area under curve (AUC) of 0.604 (95% CI: 0.568~0.641) in predicting no-reflow phenomenon, and PIA had an AUC of 0.574 (95% CI: 0.537 to 0.611). Importantly, the new signature combining D-dimer level on admission and PIA showed an increased AUC (0.637, 95%CI: 0.601 to 0.673) in predicting the no-reflow phenomenon. Moreover, the patients with high D-dimer level on admission but without PIA had significantly increased ratio of no-reflow phenomenon and in-hospital mortality compared to the other patients (P<0.001 and P=0.041, respectively). CONCLUSIONS Based on these solid results, we conclude that combining plasma D-dimer level on admission and PIA might create a good signature for use in predicting the no-reflow phenomenon after primary PCI in STEMI patients.

Impact of hepatitis B virus (HBV) infection on platelet response to clopidogrel in patients undergoing coronary stent implantation.

BACKGROUND: Hepatitis B virus (HBV) infection has been reported to down-regulate the expression of CYP2C19 gene, which may decrease the bioactivation of clopidogrel into active metabolites. We aimed to evaluate the impact of HBV infection on platelet response to clopidogrel in patients undergoing coronary stent implantation. METHODS: A total of 1805 patients who had received coronary stent implantation and taken aspirin 100 mg in combination with clopidogrel 75 mg daily ≥5 days were consecutively recruited. The serologic identifications for HBV, platelet aggregations in response to arachidonic acid (PLAA) and adenosine diphosphate (PLADP), as well as ABCB1, CYP2C19, CYP3A5, PON1 and P2RY12 genotypes were determined. Clopidogrel low response (CLR) was defined as PLADP > 40%. RESULTS: Among the recruited subjects, 102 patients showed hepatitis B surface antigen (HBsAg) positive and 1703 patients negative. PLADP was significantly higher in HBsAg positive group than that in HBsAg negative group [38 (24-48) % vs. 29 (20-39) %, p < 0.001] while the difference of PLAA was not statistically significant (p = 0.329). The incidence of CLR was significantly higher in HBsAg positive group compared with that in HBsAg negative group (43.1% vs. 23.4%, p < 0.001). After adjusted for CYP2C19 genotype and known risk factors, HBsAg positive patients exhibited a significantly higher risk of CLR (adjusted odds ratio: 2.81, 95% confidence interval: 1.73 to 4.58, p < 0.001). CONCLUSIONS: HBV infection is an independent risk factor of CLR, in addition to CYP2C19 gene mutations. (Pharmacogenetic and Pharmacokinetic Study of Clopidogrel; NCT01968499).