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Background and Purpose: Although the amphiphilic nature of the widely used antithrombotic drug Ticagrelor is well known, it was never considered as a membranotropic agent capable of interacting with the lipid bilayer in a receptor‐independent way. In this study, we investigated the influence of Ticagrelor on plasma membrane lipid order in platelets and if this modulates the potency of Ticagrelor at the P2Y12 receptor. Experimental Approach: We combined fluorescent in situ, in vitro and in silico approaches to probe the interactions between the plasma membrane of platelets and Ticagrelor. The influence of Ticagrelor on the lipid order of the platelet plasma membrane and large unilamellar vesicles was studied using the advanced fluorescent probe NR12S. Furthermore, the properties of model lipid bilayers in the presence of Ticagrelor were characterized by molecular dynamics simulations. Finally, the influence of an increased lipid order on the dose‐response of platelets to Ticagrelor was studied. Key Results: Ticagrelor incorporates spontaneously into lipid bilayers and affects the lipid order of the membranes of model vesicles and isolated platelets, in a nontrivial composition and concentration‐dependent manner. We showed that higher plasma membrane lipid order in platelets leads to a lower IC50 value for Ticagrelor. It is shown that membrane incorporation of Ticagrelor increases its potency at the P2Y12 receptor, by increasing the order of the platelet plasma membrane. Conclusion and Implications: A novel dual mechanism of Ticagrelor action is suggested that combines direct binding to P2Y12 receptor with simultaneous modulation of receptor‐lipid microenvironment. [ABSTRACT FROM AUTHOR]

When Berger et al. first reported IgA nephropathy in 1968, the prognosis was generally thought to be benign. However, as more case data were accumulated, it became evident that not all patients with IgA nephropathy necessarily had a good prognosis. IgA nephropathy has a significant morbidity, culminating in end‐stage kidney disease (ESKD) in about 40% of patients without treatment within 20 years of the diagnosis. Although almost 20% of patients remain stable in their renal function, 30%–40% of patients develop ESKD from its onset. The important factors of renal outcome in patients with IgA nephropathy is the severity of histopathological findings, heavy proteinuria, long duration of proteinuria, haematuria and hypertension. [ABSTRACT FROM AUTHOR]

Background: Antiplatelet therapy is used to decrease the risk of graft failure post coronary artery bypass graft surgery. We aimed to compare dual antiplatelet therapy (DAPT) with monotherapy along with a comparison of Aspirin, Ticagrelor, Aspirin+Ticagrelor (A+T) and Aspirin+Clopidogrel (A+C) to determine the major and minor bleeding risk, risk of postoperative myocardial infarction (MI), stroke, and all-cause mortality (ACM). Methods: Randomized Controlled Trials comparing the four groups were included. Odds ratio (OR) and Absolute Risk (AR) were employed to assess the mean and standard deviation (SD) with 95% confidence intervals (CI). The Bayesian random-effects model was used for statistical analysis. Risk difference and Cochran Q tests were used to calculate rank probability (RP) and heterogeneity, respectively. Results: We included 10 trials, consisting of 21 arms and 3926 patients. For the risk of major and minor bleed, A + T and Ticagrelor showed the lowest mean value of 0.040 (0.043) and 0.067 (0.073), respectively, and the highest RP of being the safest group. While a direct comparison between DAPT and monotherapy resulted in an OR of 0.57 [0.34, 0.95] for the risk of minor bleed. A + T was found to have the highest RP and the lowest mean value in terms of ACM, MI, and stroke. Conclusion: No significant difference was found between monotherapy or dual-antiplatelet therapy for the major bleeding risk safety outcome, however DAPT was found to have a significantly higher rate of minor bleeding complications post-CABG. DAPT should be considered as the antiplatelet modality of choice post-CABG. [ABSTRACT FROM AUTHOR]

Platelet aggregation is a complicated process mediated by different signaling pathways. As the process is highly complex and apparently redundant, the relationships between these pathways are not yet fully known. The aim of this project was to study the interconnections among seven different aggregation pathways in a group of 53 generally healthy volunteers aged 20 to 66 years. Platelet aggregation was induced with thrombin receptor activating peptide 6 (TRAP), arachidonic acid (AA), platelet activating factor 16 (PAF), ADP, collagen, thromboxane A2 analogue U46619 or ristocetin (platelet agglutination) ex vivo in fasting blood samples according to standardized timetable protocol. Additionally, some samples were pre-treated with known clinically used antiplatelet drugs (vorapaxar, ticagrelor or acetylsalicylic acid (ASA)). Significant correlations among all used inducers were detected (Pearson correlation coefficients (rP): 0.3 to 0.85). Of all the triggers, AA showed to be the best predictor of the response to other inducers with rP ranging from 0.66 to 0.85. Interestingly, the antiplatelet response to ticagrelor strongly predicted the response to unrelated drug vorapaxar (rP = 0.71). Our results indicate that a response to one inducer can predict the response for other triggers or even to an antiplatelet drug. These data are useful for future testing but should be also confirmed in patients. [ABSTRACT FROM AUTHOR]

Background: As there is no consensus on the impact of antithrombotic drugs on post-gastrectomy outcomes in gastric cancer patients, this study aimed to investigate the impact of antithrombotic drugs on postoperative outcomes in these patients after gastrectomy. Methods: Patients with Stage I–III primary gastric cancer who underwent radical gastrectomy between April 2005 and May 2022 were included. We performed propensity score matching to adjust for patient background and compared bleeding complications. Multivariate analysis with logistic regression analysis was performed to identify risk factors associated with bleeding complications. Results: Of the 6798 patients, 310 (4.6%) were in the antithrombotic group and 6488 (95.4%) were in the non-antithrombotic group. Twenty-six patients (0.38%) experienced bleeding complications. After matching, the number of patients in each group was 300, with insignificant differences in any factor. A comparison of postoperative outcomes showed no difference in bleeding complications (P = 0.249). In the antithrombotic group, 39 (12.6%) continued drugs, and 271 (87.4%) discontinued them before surgery. After matching, there were 30 and 60 patients, respectively, with no differences in patient background. A comparison of postoperative outcomes showed no differences in bleeding complications (P = 0.551). In multivariate analysis, antithrombotic drug use and continuation of antiplatelet agents were not risk factors for bleeding complications. Conclusion: Antithrombotic drugs and its continuation may not worsen bleeding complications in patients with gastric cancer after radical gastrectomy. Bleeding complications were rare, and further studies are needed on risk factors for bleeding complications in larger databases. [ABSTRACT FROM AUTHOR]

The process of platelet aggregation is often influenced by several factors including sex and age. A literature review confirmed the existence of sex-related differences in platelet aggregation. Although 68 out of 78 papers found such differences, there are still some controversies regarding these differences, which can be due to multiple factors (age, trigger, concomitant disease, sample handling, etc.). These outcomes are discussed in line with novel results obtained from a local study, in which blood samples from a total of 53 overall healthy women and men with ages ranging from 20 to 66 years were collected. Aggregation was induced with seven different triggers (ristocetin, thrombin receptor activating peptide 6 [TRAP-6], arachidonic acid [AA], platelet-activating factor 16 [PAF-16], ADP, collagen, or thromboxane A 2 analog U-46619) ex vivo. In addition, three FDA-approved antiplatelet drugs (vorapaxar, ticagrelor, or acetylsalicylic acid [ASA]) were also tested. In general, women had higher aggregation responses to some agonists (ADP, TRAP), as well as lower benefit from inhibitors (ASA, vorapaxar). The aggregatory responses to AA and TRAP decreased with age in both sexes, while responses to ADP, U-46619, and PAF were affected by age only in women. In conclusion, more studies are needed to decipher the biological importance of sex-related differences in platelet aggregation in part to enable personalized antiplatelet treatment. [ABSTRACT FROM AUTHOR]

Therapeutic peptides are oligomers or short polymers of amino acids used for various medical purposes. Peptide-based treatments have evolved considerably due to new technologies, stimulating new research interests. They have been shown to be beneficial in a variety of therapeutic applications, notably in the treatment of cardiovascular disorders such as acute coronary syndrome (ACS). ACS is characterized by coronary artery wall damage and consequent formation of an intraluminal thrombus obstructing one or more coronary arteries, leading to unstable angina, non-ST elevated myocardial infarction, and ST-elevated myocardial infarction. One of the promising peptide drugs in the treatment of these pathologies is eptifibatide, a synthetic heptapeptide derived from rattlesnake venom. Eptifibatide is a glycoprotein IIb/IIIa inhibitor that blocks different pathways in platelet activation and aggregation. In this narrative review, we summarized the current evidence on the mechanism of action, clinical pharmacology, and applications of eptifibatide in cardiology. Additionally, we illustrated its possible broader usage with new indications, including ischemic stroke, carotid stenting, intracranial aneurysm stenting, and septic shock. Further research is, however, required to fully evaluate the role of eptifibatide in these pathologies, independently and in comparison to other medications. [ABSTRACT FROM AUTHOR]

Ticagrelor is a BCS class IV drug that inhibits platelet action by reversibly binding to the P2Y12 receptor. One of the major challenges faced by the class IV (low solubility, low permeability) drug is the lower dissolution rate leading to low bioavailability. The bioavailability of the marketed formulation of ticagrelor is approximately 36%. Researchers have come up with various techniques to improve the BCS class II and IV drug formulations as an integral part of the development of the pharmaceutical sciences. An increase in solubility can be achieved by various methods such as Salt formation, Complexation, Micronization, Solid Dispersion, altering the pH, Co-solvency, co-crystals, polymeric micelles, etc. A highly efficacious technique is converting a crystalline drug to its amorphous form. An extensive literature search was conducted using various databases like science direct, Taylor and Francis, Springer to extract relevant articles. Keywords like "Ticagrelor", "low permeability", "P2Y12 receptor inhibitor" were used for the literature search. Relevant articles were screened and referred for further study. This article discusses the techniques employed to increase the solubility of ticagrelor, thus highlighting the research conducted and reported. The increase in bioavailability of ticagrelor could be seen when formulated as nanoparticles, co-crystals, ticagrelor loaded self-micro emulsifying and nano emulsifying drug delivery system, solid dispersion, etc. the conversion of the crystalline drug into amorphous drug is a highly recommended approach to increase the solubility of ticagrelor which can be seen in cases of co-crystals and solid dispersion formulation. [ABSTRACT FROM AUTHOR]

Background: Ticagrelor or prasugrel are recommended to reduce ischemic events in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI). However, in clinical practice, patients are often switched from a potent P2Y12 inhibitor to clopidogrel prior to or at discharge ('de-escalation'). We sought to assess the incidence and predictors of de-escalation.Methods: Consecutive patients who received either a ticagrelor or prasugrel loading dose for AMI PCI at two tertiary centers between Jan 2015-Mar 2019 who survived to discharge were included. Data were obtained from the electronic health record and institutional NCDR CathPCI data. Patients who were de-escalated to clopidogrel were compared with those who remained on potent P2Y12 inhibitors through the time of discharge.Results: Of the1818 patients in the cohort, 1146 (63%) were de-escalated. Patients in the de-escalation group were older, more often Black, had lower prevalence of co-morbidities, less often had private insurance, and had less complex PCI. After adjustment, older age remained positively associated (OR 1.2, CI 1.08-1.34, p = .001) and Caucasian race (OR 0.5, CI 0.33-0.77, p = .002), prior MI (OR 0.7, CI 0.5-0.97, p = .032), bifurcation lesion (OR 0.71, CI 0.53-0.95, p = .019), and greater number of stents (OR 0.82, CI 0.75-0.91, p = .0001) were negatively associated with de-escalation. In de-escalated patients, the rationale was not documented in 75.9% of cases.Conclusions: De-escalation occurred frequently in patients with AMI and was associated with both non-clinical and clinical factors. Medical decision making was poorly documented and represent an area for improvement. [ABSTRACT FROM AUTHOR]

Spontaneous coronary intramural hematoma (SCIH) was one type of spontaneous coronary artery dissection without obvious intimal tear, which is easy to misdiagnose. We aimed to study the characteristics, management, and prognosis of SCIH in our center. All the SCIH patients (n = 30) diagnosed by coronary angiography from January 1, 2012 to December 31, 2018 were enrolled. The demographic characteristics, history, therapy, and follow-up were collected. The mean age of the patients was 51.8 ± 9.5 years. Most of the patients were females (66.7%) with hypertension. Patients with diffuse lesion, focal lesion, and multiple vessels were 70%, 13.3%, and 16.7%, respectively. Conservative treatment was the first choice (76.7%). The mean follow-up time was 29.3 ± 13.5 months. None of the patients had unplanned readmission due to worsening symptoms. Nine patients underwent coronary artery computed tomography reexamination after 10.3 ± 7.5 months, which showed complete recovery of SCIH. Eight patients were hospitalized for coronary angiography 6.4 ± 4.7 months later, which did not show any sign of SCIH. Spontaneous coronary intramural hematoma was most common in post-menopausal women with hypertension. Possibly, antiplatelet drugs should be avoided in SCIH. Waiting for the hematoma to heal was preferable and had a good prognosis. [ABSTRACT FROM AUTHOR]

Patients undergoing coronary artery bypass graft (CABG) surgery or carotid endarterectomy (CEA) continue antiplatelet therapy perioperatively, which may increase bleeding risk. We aimed to investigate whether Rotational thromboelastometry (ROTEM®) platelet, a newly marketed platelet function analysis, would detect antiplatelet therapy in CABG and CEA patients; whether detection of reduced platelet function was associated with increased bleeding; and whether ex vivo desmopressin increased platelet function. We included 20 CABG patients continuing aspirin and 20 CEA patients continuing clopidogrel (n = 1) or clopidogrel and aspirin (n = 19). Platelet function was analyzed with ROTEM®platelet and light transmission aggregometry (LTA). According to the lower reference limit, ROTEM®platelet managed to detect aspirin, but clopidogrel detection was inadequate compared to LTA. Using a previously published cut-off for bleeding risk, 6 (30%) patients receiving aspirin and 4 (21%) patients receiving both clopidogrel and aspirin demonstrated platelet function below this cut-off. One of the four CEA patients below the cut-off died from intracerebral hemorrhage postoperatively. CABG patients below (n = 6) and above (n = 14) the cut-off did not differ in chest tube output (median [range]: 373 ml [250–900] vs. 368 ml [195–820]). Ex vivo addition of desmopressin did not increase platelet function. In conclusion, ROTEM®platelet does reveal aspirin treatment whereas clopidogrel treatment is most often overlooked. Due to low bleeding in the study population, it was not possible to conclude on the association with bleeding risk. [ABSTRACT FROM AUTHOR]

Background: The decision-making on antiplatelet drug withdrawal or continuation before performing a pleural procedure is based on the balance between the risk of bleeding associated with the antiplatelet therapy and the risk of arterial thrombosis due to its interruption. Knowledge on antiplatelet therapy-associated risk of bleeding after pleural procedures is lacking.Research Question: Is the risk of bleeding associated with antiplatelet drugs increased in patients undergoing pleural procedures?Study Design and Methods: We conducted a French multicenter cohort study in 19 centers. The main outcome was the occurrence of bleeding, defined as hematoma, hemoptysis, or hemothorax, during the 24 h following a pleural procedure. Serious bleeding events were defined as bleeding requiring blood transfusion, respiratory support, endotracheal intubation, embolization, or surgery, or as death.Results: A total of 1,124 patients was included (men, 66%; median age, 62.6 ± 27.7 years), of whom 182 were receiving antiplatelet therapy and 942 were not. Fifteen patients experienced a bleeding event, including eight serious bleeding events. The 24-h incidence of bleeding was 3.23% (95% CI, 1.08%-5.91%) in the antiplatelet group and 0.96% (95% CI, 0.43%-1.60%) in the control group. The occurrence of bleeding events was significantly associated with antiplatelet therapy in univariate analysis (OR, 3.44; 95% CI, 1.14-9.66; P = .021) and multivariate analysis (OR, 4.13; 95% CI, 1.01-17.03; P = .044) after adjusting for demographic data and the main risk factors for bleeding. Likewise, antiplatelet therapy was significantly associated with serious bleeding in univariate analysis (OR, 8.61; 95% CI, 2.09-42.3; P = .003) and multivariate analysis (OR, 7.27; 95% CI, 1.18-56.1; P = .032) after adjusting for the number of risk factors for bleeding.Interpretation: Antiplatelet therapy was associated with an increased risk of post-pleural procedure bleeding and serious bleeding. Future guidelines should take into account these results for patient safety. [ABSTRACT FROM AUTHOR]

Purpose: The effectiveness of Electronic Medication Packaging devices for monitoring drug adherence has been widely reported. However, conventional devices are expensive for routine use and cannot confirm whether the medication was administered. We aimed to determine, in a pilot and feasibility study, the impact of introducing a new medication support device, the Pletaal Assist System®, to monitor and improve cilostazol adherence for stroke prevention at an outpatient clinic. Patients and Methods: We assessed consecutive patients treated with cilostazol for > 3 months at our stroke outpatient clinic from January 2018 to March 2020. The adherence rate was assessed as follows: (the number of pills prescribed minus the number of remaining pills)/the number of pills prescribed. We compared the adherence rates before, during, and after Pletaal Assist System® usage, respectively. Results: Overall, 25 patients (median age, 68.5 years; range, 51– 86 years; male, 64%) were enrolled. All participants were prescribed cilostazol (100 mg) twice a day. There was no significant difference in the adherence rate among the three periods. However, in 10 patients with adherence rate below 100%, the adherence rate during Pletaal Assist System® usage was higher than before usage (99.5% vs 95%, p=0.04), and the rate after using the Pletaal Assist System® tended to be lower compared to the rate during usage (99.5% vs 96%, p=0.05). Conclusion: Our preliminary evidence suggest that the Pletaal Assist System® could further improve cilostazol adherence in outpatients with poor drug adherence and may reduce the risk of recurrent strokes by improving adherence of patients with a history of stroke. [ABSTRACT FROM AUTHOR]

Study Objectives: By modifying the apneic threshold, the antiplatelet agent ticagrelor could promote central sleep apnea hypopnea syndrome (CSAHS). We aimed to assess the association between CSAHS and ticagrelor administration.Methods: Patients were prospectively included within 1 year after acute coronary syndrome (ACS), if they had no heart failure (and left ventricular ejection fraction ≥ 45%) and no history of sleep apnea. After an overnight sleep study, patients were classified as "normal" with apnea hypopnea index (AHI) < 15, "CSAHS patients" with AHI ≥ 15 mostly with central sleep apneas, and "obstructive sleep apnea hypopnea syndrome (OSAHS) patients" with AHI ≥ 15 mostly with obstructive sleep apneas.Results: We included 121 consecutive patients (mean age 56.8 ± 10.8, 88% men, mean body mass index 28.3 ± 4.4 kg/m2, left ventricular ejection fraction 56 ± 5%, at a mean of 67 ± 60 days (median 40 days, interquartile range: 30-80 days) after ACS. In total, 49 (45.3%) patients had AHI ≥ 15 (27 [22.3%] CSAHS %, 22 [18.2%] OSAHS). For 80 patients receiving ticagrelor, 24 (30%) had CSAHS with AHI ≥ 15, and for 41 patients not taking ticagrelor, only 3 (7.3%) had CSAHS with AHI ≥ 15 (chi-square = 8, p = 0.004). On multivariable analysis only age and ticagrelor administration were associated with the occurrence of CSAHS, (p = 0.0007 and p = 0.0006).Conclusion: CSA prevalence after ACS is high and seems promoted by ticagrelor administration. Results from monocentric study suggest a preliminary signal of safety. CLINICAL TRIALS.Gov Id: NCT03540459. [ABSTRACT FROM AUTHOR]

Objective: Cerebral vasospasm and delayed cerebral ischemia (DCI) are considered complications after aneurysmal subarachnoid hemorrhage (aSAH). Several hypotheses involving platelet activation have been asserted in the pathophysiology of cerebral vasospasm and DCI. This study aimed to investigate the effect of dual antiplatelet treatment (DAPT) on symptomatic vasospasm and DCI in patients with aSAH. Methods: A retrospective study was conducted on patients with aSAH from 2009 to 2018. The patients are divided into 2 groups according to the treatment method such as simple or balloon-assisted coil embolization group (SB coiling), and stentassisted coil embolization group. Patients treated by SB coiling without DAPT were classified as the control group. Patients who required dual antiplatelet treatment due to stent-assisted coil embolization were classified as DAPT group. The incidence of symptomatic vasospasm and DCI was compared between the two groups. Results: Of 743 patients with aSAH, 563 patients were treated with clipping, 115 patients treated with SB coiling, and 65 patients receive stent-assisted coiling. Among 115 patients underwent SB coiling, 14 patients were excluded by the exclusion criteria. Total number of control group (SB coiling) was 101, DAPT group (stentassisted coiling) was 65. Depending on whether or not taking DAPT, the incidence of symptomatic vasospasm was lower in the DAPT group (p=0.010). DCI incidence was also lower in the DAPT group, which was statistically significant (p=0.029). Conclusions: DAPT reduces the frequency of symptomatic vasospasm and DCI in patients with aSAH in our single-center study. To warranting this topic, further, larger prospective and randomized studies should be needed. [ABSTRACT FROM AUTHOR]

Recurrent spontaneous abortion (RSA) is defined as the loss of at least two consecutive pregnancies before the 28th week of gestation. RSA is a complicated pathological condition causedmultiple factors including genetic abnormalities, anatomical factors, endocrine disorders, immune abnormalities, prethrombotic state (PTS) and infection factors. Studies have suggested that anticoagulation and antiplatelet therapy could significantly improve the pregnancy outcomes of RSA patients with PTS and autoimmune abnormalities. Frequently used anticoagulants and antiplatelet drugs are heparin, heparinoid, warfarin, aspirin and clopidogrel. However, the maternal and fetal safety after the of these drugs during pregnancy has long been concerned. Safety of anticoagulants and antiplatelet drugs in patients with recurrent spontaneous abortion during pregnancy is reviewed. [ABSTRACT FROM AUTHOR]

BACKGROUND: One of the concerns in patients with acute ischemic stroke with former history of taking antiplatelet drugs is the risk of intracerebral hemorrhage following venous thrombolysis. The purpose of this study was to evaluate the effect of previous administration of antiplatelet drugs on adverse outcomes of recombinant tissue plasminogen activator (tPA) in patients with acute ischemic stroke. METHODS: In this study, 46 patients with the diagnosis of acute ischemic stroke were recruited. Patients were assessed in a period of three hours after stroke and received the standard dose of tPA (0.9 mg/kg). History of antiplatelet drugs, risk factors, demographic information and stroke severity were collected. The severity of the stroke was determined by the National Institutes of Health Stroke Scale (NIHSS). The outcome was assessed using the Modified Rankin Scale (MRS) and Barthel Index (BI) in the days one, 14 and 90. RESULTS: Patients with history of antiplatelet drugs had an increased rate of intracranial hemorrhage [odds ratio (95% CI) = 7.3 (1.3–40.5)]. Stroke severity scores were higher in patients receiving antiplatelet drugs than the other group at discharge day and day 90. In both groups, the severity of the disease decreased with time. Mortality rate was 42.1% in patients received antiplatelet drugs and 18.5% in the other group (P > 0.05). CONCLUSION: Based on the results of this study, patients with acute ischemic stroke and history of taking antiplatelet drugs have poor outcome following administration of standard dose of tPA. [ABSTRACT FROM AUTHOR]

Our previous acute dual study (ADS) reported that dual antiplatelet therapy (DAPT) using cilostazol and aspirin did not reduce the rate of neurological deterioration in non-cardioembolic stroke patients. In this post-hoc analysis, we investigated whether the impact of dual antiplatelet therapy (DAPT) may depend on neurological severity, as represented by large artery disease. Neurological deterioration was defined as neurological progression with an increment of the National Institutes of Health Stroke Scale (NIHSS) score of ≥2. NIHSS score subgroups were divided into that of 0–1, 2–4, 5–10, and >10. Among 1014 patients, 203 (20%) had the large artery disease, and 811 (80%) did not. In the total cohort, the rate of neurological deterioration was 10.8% in the DAPT group and 8.3% in the aspirin group (P = 0.197). When we focused on the large artery disease group, DAPT group had a higher rate of neurological deterioration as 18.3% compared to 8.2% in the aspirin group (P = 0.036). Among patients with NIHSS score of 0–1 and 2–4, the rates of neurological deterioration were not different between the two group (both, P = 1.000). However, when NIHSS score elevated to 5–10, 45% in the DAPT group and 9.1% in the aspirin group deteriorated (P = 0.013). Among the patients with NIHSS score of >10, 60% in the DAPT group and none (0%) in the aspirin group had the neurological deterioration (P = 0.045). DAPT with aspirin and cilostazol was associated with higher rate of neurological deterioration when patients have large artery disease and not mild neurological deficits. • Whether the impact of dual antiplatelet therapy (DAPT) using cilostazol may depend on the neurological severity was studied. • Neurological deterioration was defined as neurological progression with an increment of the NIHSS score of ≥2. • In patients with large artery disease, DAPT group had a higher rate of progression compared to the aspirin group. • In patients with NIHSS score of 5–10, 45% in the DAPT group and 9.1% in the aspirin group deteriorated. • DAPT using cilostazol was associated with progression when patients have large artery disease and not mild neurological deficits. [ABSTRACT FROM AUTHOR]

The maintenance dose of prasugrel (PRAS) for neuroendovascular treatment requires much research. We report the antiplatelet effect of PRAS measured by VerifyNow P2Y12 reaction units (PRUs) in patients during the perioperative period of neuroendovascular treatment.Between January 2017 and January 2023, 230 patients who underwent endovascular treatment for unruptured intracranial aneurysms or carotid artery stenosis at our institution were retrospectively identified. Patients received dual antiplatelet therapy with 100 mg aspirin (ASA) and 75 mg clopidogrel (CLP)/day (CLP group, n = 186) or 100 mg ASA and 3.75 mg PRAS/day (PRAS group, n = 44) 2 weeks before the procedures. The PRU value was compared between the CLP and PRAS groups. In the study, we defined 95≦PRU < 208 as the optimal range. Perioperative complications within seven days of surgery were also analyzed.The mean value of PRU was significantly low in the PRAS group (179.13 ± 66.03 in CLP vs. 154.75 ± 54.01 in PRAS, p = 0.024). The proportion of the patients who exhibited 95≦PRU < 208 was significantly higher in the PRAS group (55.4% vs. 72.7%, p = 0.036). Ischemic and hemorrhagic complication rates were not significantly different between the CLP and PRAS groups (7.6% vs. 0%, p = 0.076; 4.7% vs. 0%, p = 0.361). The ischemic complication rate was higher in patients with a PRU > 208 than in those with PRU < 208 (12.5% vs. 3.8%, p = 0.044). The hemorrhagic complication rate was not significantly different between the PRU < 95 and 95≦PRU groups (8.4% vs. 3.2%, p = 0.224).Maintenance dose PRAS further decreased the PRU value and reached the optimal range in more cases than CLP during the perioperative period of neuroendovascular treatment. Ischemic complications significantly increased in the 208 < PRU group. [ABSTRACT FROM AUTHOR]

• Cilostazol is used in practice for the management of peripheral arterial disease. • A generic formulation of cilostazol was compared (C max , AUC, T max) with the brand-name product. • No statistically significant differences were found in either the bioavailability or safety profiles of the two products. • The generic version could increase Thai patients' access to cilostazol. Cilostazol is a vasodilator with anticoagulant effect for treatment of peripheral vascular disease. Cilostazol 100-mg tablet was shown to increase walking distance in this patient population. The aim of this study was to investigate and compare the pharmacokinetic profiles and safety of Bestazol 100-mg tablet (Berlin Pharmaceutical Industry Co Ltd, Bangkok, Thailand), which is a generic formulation of cilostazol, with the original brand Pletaal 100-mg tablet (Korea Otsuka Pharmaceutical Co Ltd, Seoul, South Korea) in healthy Thai adult volunteers. The pharmacokinetic profiles of Bestazol (test) and Pletaal (reference) 100-mg tablets were compared in a single-dose, open-label, 2-treatment, 2-period, 2-sequence, randomized crossover study in healthy Thai adult volunteers. This study was conducted at the Siriraj Clinical Research Center, Siriraj Hospital, Mahidol University, Bangkok, Thailand. Each volunteer was initially treated according to either the test–reference or the reference–test sequence, after which each volunteer was switched to the other study sequence after a 2-week washout period. Pharmacokinetic analysis was performed using log-transformed ratios for C max , AUC 0–last , AUC 0–∞, T max , t 1/2 , and λ Z for both cilostazol and 3,4-dehydro-cilostazol (its active metabolite) with 90% CI. Physical examination, clinical laboratory data, vital signs, and adverse events were assessed in all participants. A total of 28 volunteers were included in the final analysis. The ratios of the geometric mean and the 90% CI compared test to reference of cilostazol formulations and were 101.86% (90% CI, 91.88%–112.92%), 107.78% (90% CI, 99.67%–116.56%), and 110.46% (90% CI, 102.68%–118.82%) for C max , AUC 0–last , and AUC 0–∞ , respectively. The ratios of the geometric mean and the 90% CI compared test to reference of 3,4-dehydro-cilostazol and were 106.72% (95% CI, 95.31%–119.50%), 110.54% (95% CI, 101.92%–119.89%), and 107.37% (95% CI, 96.74%–119.16%) for C max , AUC 0–last , and AUC 0–∞ , respectively. No significant difference was observed between formulations for T max. The most common adverse event was headache (51.85%), with no significant difference in incidence between the test and reference groups. No serious adverse events related to the studied drugs were reported. The findings of this study indicate these 2 cilostazol tablet formulations to be bioequivalent. Bestazol 100-mg tablet was bioequivalent to Pletaal 100-mg tablet. Thus, the formulations can be used interchangeably in clinical practice. [ABSTRACT FROM AUTHOR]

Abstract Background Gastrointestinal bleeding (GIB) is burdened by high mortality rate that increases with aging. Elderly patients may be exposed to multiple risk factors for GIB. We aimed at defining the impact of GIB in elderly patients. Methods Since 2008, samples of elderly patients (age ≥ 65 years) with multimorbidity admitted to 101 internal medicine wards across Italy have been prospectively enrolled and followed-up (REPOSI registry). Diagnoses of GIB, length of stay (LOS), mortality rate, and possible risk factors, including drugs, index of comorbidity (Cumulative Illness Rating Scale [CIRS]), polypharmacy, and chronic diseases were assessed. Adjusted multivariate logistic regression models were computed. Results 3872 patients were included (mean age 79 ± 7.5 years, F:M ratio 1.1:1). GIB was reported in 120 patients (mean age 79.6 ± 7.3 years, F:M 0.9:1), with a crude prevalence of 3.1%. Upper GIB occurred in 72 patients (mean age 79.3 ± 7.6 years, F:M 0.8:1), lower GIB in 51 patients (mean age 79.4 ± 7.1 years, F:M 0.9:1), and both upper/lower GIB in 3 patients. Hemorrhagic gastritis/duodenitis and colonic diverticular disease were the most common causes. The LOS of patients with GIB was 11.7 ± 8.1 days, with a 3.3% in-hospital and a 9.4% 3-month mortality rates. Liver cirrhosis (OR 5.64; CI 2.51–12.65), non-ASA antiplatelet agents (OR 2.70; CI 1.23–5.90), and CIRS index of comorbidity >3 (OR 2.41; CI 1.16–4.98) were associated with GIB (p < 0.05). Conclusions A high index of comorbidity is associated with high odds of GIB in elderly patients. The use of non-ASA antiplatelet agents should be discussed in patients with multimorbidity. Highlights • Gastrointestinal bleeding (GIB) was present in 120/3872 elderly patients (3.1%). • Patients with GIB had a 3.3% in-hospital and a 9.4% 3-month mortality rate. • An index of comorbidity >3 was significantly associated with GIB (OR 2.41). • Antiplatelet therapy should be carefully discussed in patients with multimorbidity. [ABSTRACT FROM AUTHOR]

Acquired factor V inhibitor (AFVI) is a rare coagulopathy. It may be triggered by specific antigens such as antibiotics. We herein report the first case of AFVI after treatment with prasugrel hydrochloride (prasugrel) in an 80-year-old male who underwent percutaneous coronary intervention because of angina pectoris 6 years ago and was initiated on aspirin and ticlopidine hydrochloride. He was switched from ticlopidine hydrochloride to prasugrel before undergoing percutaneous coronary intervention for myocardial infarction. Fifteen days later, he developed sudden nasal hemorrhage, hematuria, and systemic purpura. Coagulation tests revealed prolonged prothrombin time-international normalized ratio (11.35) and activated partial thromboplastin time (170 s). The coagulation factor profile revealed a decreased FV activity (1%). The Bethesda assay for FV inhibitor was positive. AFVI was diagnosed; prasugrel was immediately discontinued, and administration of recombinant activated factor VII and prednisolone were initiated. Hemorrhagic symptoms immediately disappeared; FV activity improved, and the FV inhibitor titer was normalized. [ABSTRACT FROM AUTHOR]

Venomous and hematophagous animals use their venom or saliva for survival, to obtain food, and for self-defense. Venom and saliva from these animals are cocktails of bioactive molecules primarily composed of proteins and peptides. These molecules are called toxins because they cause unwanted consequences on prey. They exhibit unique, diverse, and specific biological activities that perturb normal physiological processes of their prey and host. However, the potential of toxins as inspirations for the development of therapeutic agents or pharmacological tools has also long been recognized. In addition to their small size, the exquisite selectivity and structural stability of toxins make them attractive as starting molecule in the development of therapeutic and diagnostic agents. Drug discovery and development from venomous and hematophagous animals against cardiovascular diseases have been particularly successful. Some of the notable success include antihypertensive (captopril and enalapril) and antiplatelet agents (tirofiban and eptifibatide), as well as anticoagulants (lepirudin and bivalirudin). Highlighted in this review are many venom or saliva-derived cardiovascular-active proteins and peptides of therapeutic interest, including those that are currently in preclinical stages and those that have been approved by FDA and currently in the market. The authors attempt to summarize their structure, function, mechanism of action, and development with respect to cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Cardiovascular disease, which is caused by unregulated platelet aggregation, is one of the main causes of deaths worldwide. Many studies have focused on natural products with antiplatelet effects as a safe alternative therapy to prevent the disease. In this context, an in-house chemical library was screened to find natural products capable of inhibiting the interaction between platelet integrin αIIbβ3 and fibrinogen, which is an essential step in platelet aggregation. On the basis of the screening results, indothiazinone, an alkaloid found in microbial cultures, was identified as a potential antiplatelet agent. Specifically, indothiazinone treatment significantly inhibited the binding of fibrinogen to Chinese hamster ovary cells expressing integrin αIIbβ3. It also restricted thrombin- and adenosine diphosphate-dependent spreading of human platelets on a fibrinogen matrix. More importantly, surface plasmon resonance and molecular dynamics studies suggested that indothiazinone suppressed talin-induced activation of integrin αIIbβ3 presumably by inhibiting talin-integrin interaction. In conclusion, these results suggest that indothiazinone can be used as a lead compound for the development of antiplatelet drugs with a novel mode of action. [ABSTRACT FROM AUTHOR]

Background Although antithrombotic agents are widely used for cardiac and cerebrovascular disease prevention, they increase the risk of gastrointestinal (GI) bleeding. Objective To examine GI bleeding risk in association with an esophagogastroduodenoscopy (EGD) biopsy performed in patients without cessation of antithrombotic therapy. Methods This study was prospectively conducted at 14 centers. EGD biopsies were performed in patients receiving antithrombotic agents without cessation, as well as age- and sex-matched controls not receiving antithrombotic therapy. Patients treated with warfarin before the biopsy had a prothrombin time-international normalized ratio level <3.0. The proportion of GI bleeding events was compared between the groups. Results The patient group (n = 277) underwent a total of 560 biopsies while continuing antithrombotic therapy, of whom 24 were receiving multiple antiplatelet drugs, and 9 were receiving both antiplatelet and anticoagulant agents. The control patients (n = 263) underwent 557 biopsies. The upper-GI bleeding rate within 30 days after the EGD biopsy did not increase in patients without cessation of antithrombotic treatment, regardless of receiving single or multiple antithrombotic agents. Conclusions We found no significant increase in upper-GI bleeding risk following an EGD biopsy in patients taking antithrombotic agents, suggesting its safety without the need for antithrombotic treatment interruption. [ABSTRACT FROM AUTHOR]

Non-traumatic convexal subarachnoid hemorrhage (CSAH) is a comparatively infrequent with various vascular and nonvascular causes, it rarely occurs concomitant to acute ischemic stroke. We report a case of a 59-year-old woman, visited emergency room with right side subjective weakness spontaneously. Magnetic resonance diffusion-weighted images revealed an acute infarction of anterior cerebral arterial territory. Computed tomographic angiography showed a left frontal CSAH without any vascular lesions. And other laboratory studies were non-specific. We treated with dual antiplatelet drugs (cilostazole [Otsuka Pharmaceutical Co., Ltd. tokyo, Japan] and Aspirin [Bayer Pharma AG., Leverkusen, Germany]). She has done well for a follow-up period. (5 months) This case demonstrates the CSAH with acute infarction is rare but need to work up to identify the etiology and antiplatelet dugs are taken into account for treatments. [ABSTRACT FROM AUTHOR]

In a developing country, where patient access to tertiary care is limited and most patients have to pay out of pocket, it is imperative for the physicians to practice evidence-based medicine. Reports on prescription details and surveys are not available. The aim of this study is to describe the prescribing patterns for various medications used in the treatment of stroke among the first contact physicians in North India; to estimate the proportion of patients being prescribed the non-recommended drugs and to determine any relationship between the economic status of the patient and the prescription pattern. Details of economic status, education level, type of stroke, type of hospital, qualification of treating physician and the number and nature of medications were noted from the prescriptions and patients. Two hundred and sixteen patients with ischemic stroke (71.3% males, average age 51.5 years) were included. Among poor patients,N= (36.8%) received any of the neuroprotective drugs including citicoline 19 (27.5%), piracetam 11(15.9%) and edaravone 2(2.9%). Both specialist and private hospitals are associated with higher prescription of “ineffective neuroprotective” drugs in both poor and rich patients. Reasons for overprescribing neuroprotective medications need to be studied and remedial measures need to be taken to practice evidence-based medicine. [ABSTRACT FROM AUTHOR]

Antiplatelet and antithrombotic therapies are systematically considered to prevent restenosis following coronary stent implantation. Currently, patients receiving medicated stents are prescribed to orally take anticoagulants and antiplatelet drugs such as aspirin (ASP) and prasugrel (PRAS). Propolis (PROP) known as a natural organic compound was recently evaluated for its antiplatelet activity, antibiotics and immunomodulatory activities. In this study, antiplatelet drug-coated Co–Cr substrates were prepared with biodegradable poly( d , l -lactide) (PDLLA) containing ASP, PRA, or PROP using electrospray and the blood compatibility of the different substrates was investigated by measuring protein adsorption and platelet adhesion. In addition, the anti-inflammatory properties of the modified Co–Cr surfaces were assessed by measuring IL-8 and IL-6 expression levels in human endothelial cell cultures. Drug-coated surfaces were found to resist the adsorption of fibrinogen when compared to bare Co–Cr or PDLLA-coated Co–Cr. Interestingly, ASP- and PROP-containing substrates not only showed reduced adhesion of platelets and delayed coagulation time, but also drastically reduced the expression level of IL-8 and IL-6. Such results are supported that ASP- or PROP-coated Co–Cr can be potentially used as a stent material to mitigate early stage of restenosis. The developed coating materials might be an interesting alternative to systemic anticoagulant therapies prescribed after stent implantation. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study is to analyze the results obtained using stents for the treatment of neurovascular diseases in pediatric patients. Methods: A retrospective study of 6-year period was undertaken evaluating clinical charts and imaging studies of patients treated with stents because of neurovascular diseases. Results: Nine patients were managed with 10 stents. Seven children were females. The median age was 11 years. There were four cases of broad neck cerebral aneurysms, a pseudoaneurysm of the cervical internal carotid artery, a vertebro-jugular fistula, two patients with internal carotid artery (ICA) stenosis affecting the cervical and supraclinoid segment, and a vertebral artery dissection. The only complication was a silent posterior communicating artery (PCoA) thrombosis in a PCoA aneurysm treated with two stents. Dual antiplatelet therapy was given after the procedure to avoid in stent thrombosis. Conclusion: Stents are safe and effective for treatment of neurovascular diseases in children, but studies are needed in order to protocolize the use of antiplatelet drugs in children. [ABSTRACT FROM AUTHOR]

Background: Stroke occurrence despite chronic antiplatelet drug (APD) treatment is frequent. We aimed at evaluating the relevance of platelet aggregation testing in the identification of stroke etiology in this context. Methods: Patients admitted for a suspected acute ischemic stroke, while under APD (aspirin and/or clopidogrel), were prospectively included. The efficacy of the APD was evaluated using a Multiplate™ assay. Resistance was confirmed using light transmission aggregometry. A standardized diagnostic work-up was performed to identify stroke mechanism according to the TOAST and the ASCO classifications. We evaluated the influence of APD functional status on stroke severity and identified potential determinants of resistance. Results: APD resistance was observed in 53 of the 287 patients (18.5%). No difference in stroke mechanism depending on APD efficacy was observed. Patients sensitive to APD had less severe initial stroke severity (mean National Institutes of Health Stroke Scale 3.9 ± 5.6 vs. 7.2 ± 6.8; p < 0.01). Main determinants for APD resistance were a worse control of the diabetes and higher baseline levels of inflammation (mean CRP 26.4 ± 56.0 vs. 9.3 ± 21.0; p < 0.01). Conclusions: Platelet function testing does not provide orientation concerning stroke mechanism in patients who were previously on APDs. However, the high frequency of APD resistance and its association with inflammation and stroke severity are confirmed. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Apparently trivial, one of the most frequent pathologies in neurosurgical practice, chronic subdural haematoma, continues to be achallenge for the neurosurgeons both from the therapeutic and postoperatory complications point of view, taking into account that itis frequently met in elders, who usually present a complex pathology. The fact that, by definition, there is a latent period between themoment the brain injury, usually minor, occurs and the appearance of clinical symptomatology, frequently makes the trauma beignored, this complicating the diagnosis and most of the times delaying the application of the adequate treatment.Developing slowly in time, in weeks or months, the aspect that chronic subdural haematoma usually occurs in elders should not beneglected, its clinical symptomatology often debuting with memory and attention disorders, so that the patient is usually referred topsychiatrists or neurologists, only a paraclinical investigation (CT scan or MRI) being able to establish the diagnosis.Even the appearance of the lateral signs is subjected to many diagnosis confusions because patients deny the existence of a traumain over 50% of the cases. [ABSTRACT FROM AUTHOR]

The process of platelet aggregation is often conditioned by personal circumstances such as age, gender, lifestyle, and the presence of concomitant diseases. An additional factor is the resistance to current antiplatelet drugs developed by some patients, although the reason is not always obvious. In this work, we enrolled a total of 53 overall healthy women and men donors with ages ranging from 20 to 66 years for a cross-sectional study. Blood samples were taken, and aggregation was induced with a total of seven different compounds (ristocetin, thrombin receptor activating protein-6 [TRAP], arachidonic acid [AA], platelet activating factor-16 [PAF], ADP, collagen, or thromboxane A2 analogue U46619) ex vivo. In addition, some samples were pretreated with clinically used antiplatelet drugs (vorapaxar, ticagrelor, or acetylsalicylic acid [ASA]). Our results showed a pattern in which increasing age decreased the aggregatory responses to AA and TRAP in both genders, whereas responses to ADP, U-46619, and PAF were affected by age only in women. In addition, women had stronger responses to some aggregation inducers (ADP, TRAP), as well as lower benefit from antiplatelet drugs (ASA, vorapaxar). Physiological levels of blood lipids and glucose, as well as body mass index, had mostly no effect on platelet aggregation in this study. On the contrary, several strong positive correlations between different aggregation triggers were observed. The different responses in women, in relation to age, are of note for future studies. [ABSTRACT FROM AUTHOR]

Background: The 2005 Japan Gastroenterological Endoscopy Society (JGES) guidelines for the management of antithrombotic drugs focused on the increasing risks of bleeding, even from biopsy during scheduled esophagogastroduodenoscopy (EGD). The new 2012 guidelines emphasized the prevention of thromboembolic complications. To compare with the new guidelines, we investigated the clinical management of EGD by clinicians under the former JGES guidelines for patients taking antithrombotic agents. Methods: Medical records of 4574 patients (mean age 63.4 years, range 3-96 years, male/female ratio 2805/1769) who underwent scheduled EGD from April 2011 to March 2012 were reviewed retrospectively. The prescribed agents, pre-existing comorbidities, drug cessation before EGD, bleeding, and thromboembolic complications were investigated. Results: Five hundred forty-six patients (12.0 %) were taking antithrombotic drugs (aspirin, 313; warfarin, 134; cilostazol, 57; clopidogrel, 59; ethylicosapentate, 40; prostaglandin preparations, 41; ticlopidine, 29; icosapentate, 24; dipyridamole, 4); 116 and 29 patients, respectively, were managed with a combination of 2 or 3 agents. Among 490 patients whose medical records were precisely documented, 40.6 % underwent EGD without cessation. Bleeding and thromboembolic complications were not observed. The most common pre-existing comorbidity was ischemic heart disease (27.9 %), followed by carotid or intracranial large artery atherosclerosis (20.5 %), cerebral infarction or transient ischemic attack (20.3 %), and atrial fibrillation (15.9 %). Patients with pre-existing comorbidity requiring anticoagulants frequently underwent EGD without cessation. Conclusion: We revealed the low impact of the 2005 JGES guidelines on the management of antithrombotic drugs. Our physicians have reasonably decided to continue antithrombotic drugs before EGD according to the risk of thromboembolism. [ABSTRACT FROM AUTHOR]

Objective. Not much is known about surgical management of patients with chronic subdural haematoma (CSDH) treated with antiplatelet or anticoagulant therapy. The aims of this study were to review the surgical outcomes of patients with CSDH and assess the risks of antiplatelet in their surgical management. Methods. We retrospectively analysed 448 consecutive patients with CSDH treated by one burr hole surgery at our institution. Among them, 58 patients had been on antiplatelet therapy. We discontinued the antiplatelet agents before surgery for all 58 patients. For 51 of these 58 patients (87.9%), early surgery was performed within 0-2 days from admission. We analysed the association between recurrence and patient characteristics, including history of antiplatelet or anticoagulant therapy; age (< 70 years or ≥ 70 years); side; history of angiotensin receptor II blocker, angiotensin converting enzyme blocker, or statin therapy; and previous medical history of head trauma, infarction, hypertension, diabetes mellitus, haemodialysis, seizure, cancer, or liver cirrhosis. Results. Recurrence occurred in 40 patients (8.9%), which was one of the lowest rates in the literature. Univariate analysis showed that only the presence of bilateral haematomas was associated with increased recurrence rate while antiplatelet or anticoagulant therapy did not significantly increase recurrence risk. Also, the recurrence rate from early surgery (0-2 days from drug cessation) for patients on antiplatelet therapy was not significantly higher than that from elective surgery (5 days or more after drug cessation). However, multivariate analysis revealed that previous history of cerebral infarction was an independent risk factor for CSDH recurrence. Conclusions. Our overall data support the safety of early surgery for patients on the preoperative antiplatelet therapy without drug cessation or platelet infusion. Patients with a previous history of infarction may need to be closely followed regardless of antiplatelet or anticoagulant therapy. [ABSTRACT FROM AUTHOR]

Background and purpose Cerebral ischemia and accumulation of amyloid β ( Aβ) are major risk factors for the development of dementia, including vascular dementia and Alzheimer's disease. Cilostazol, an antiplatelet drug, has been shown to improve cerebral circulation and reduce accumulation of Aβ. In this study, the long-term effect of cilostazol on cognitive function was investigated retrospectively. Methods Medical records at Sumotoitsuki Hospital were surveyed to find all patients treated with cilostazol and evaluated by the Mini-Mental State Examination ( MMSE) during at least two visits separated by an interval of more than 6 months. Patients receiving anti-dementia drugs were excluded. Temporal changes in MMSE scores were compared between patients treated with cilostazol ( n = 70) and those who ceased administration of this drug ( n = 22). The mean follow-up period was 691 days. Results Decrease in MMSE score was significantly ameliorated by administration of cilostazol. Subgroup analysis revealed that cilostazol significantly improved MMSE score in patients with mild cognitive impairment, though no significant effect was observed in patients with normal cognitive function or dementia. Conclusions Although there are limitations to such a retrospective study, these results significantly encourage undertaking a prospective cohort study to determine the effect of cilostazol on mild cognitive impairment where no treatments currently exist. [ABSTRACT FROM AUTHOR]

Antiplatelet drugs are the cornerstone of treatment for patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention. Clopidogrel and aspirin improve long-term vascular clinical outcomes in these patients and have become a standard of care. However, many patients still experience ischemic/thrombotic events, and it appears that insufficient response to both aspirin and clopidogrel contribute to this failure. Newer P2Y12 receptor blocker therapy resulted in only an approximately 2% reduction in absolute risk compared with clopidogrel. This indicates that residual ischemic events are mediated by other pathways that are unblocked by current dual antiplatelet therapy. Thrombin is the most potent platelet agonist (over 1000 times more than adenosine diphosphate on a molar basis). Thrombin-mediated platelet activation depends on protease- activated receptor (PAR) binding. PAR-1 is the main receptor for thrombin on human platelets; PAR-4 may contribute to platelet activation at much higher concentrations of thrombin. Inhibition of the PAR-1 may provide additional benefits over the standard dual antiplatelet therapy in attenuating ischemic event in patients with ACS. Vorapaxar is a new highly selective oral PAR-1 antagonist that inhibits thrombin-induced platelet activation. We review the pharmacokinetic, pharmacodynamic and clinical profile of vorapaxar. Although preliminary data indicated that vorapaxar may have the potential to improve ischemic outcomes without significantly increasing bleeding, more recent larger clinical trials seem to be less optimistic about both its effectiveness and safety. At this time, the role of vorapaxar in the settings of atherothrombotic disorders is not clear. Although it may be associated with less bleeding than P2Y12 receptor blockers, its antithrombotic effectiveness and side effects are major concerns. [ABSTRACT FROM AUTHOR]

Abstract: Cilostazol is an anti-platelet drug that reversibly inhibits phosphodiesterase III (PDE-III), which is ubiquitously expressed in platelets and various tissues. PDE-III converts cyclic adenosine monophosphate (cAMP) to 5''-AMP and up-regulates the intracellular concentration of cAMP, a potent inhibitor of platelet aggregation. Unlike other anti-platelet drugs, cilostazol is unique because patients receiving this drug do not have a significantly prolonged bleeding time, but the reasons for this difference are still unknown. In this study, we have examined how cilostazol inhibits platelet thrombus formation using anti-coagulated normal whole blood in which the platelets were labeled with a fluorescent dye in comparison with the anti-GPIIb/IIIa agent, tirofiban. We used an in vitro assay to examine mural platelet thrombus growth on a collagen surface under a high-shear rate flow in the absence of ADAMTS13 activity. These experimental conditions mimic the blood flow in patients with thrombotic thrombocytopenic purpura. Using this model, we clearly determined that cilostazol down-regulates the height of mural platelet thrombi formed on a collagen surface in a dose-dependent manner, without affecting the surface coverage. The concentration of cilostazol used in this study was relatively high (60–120μM) compared to clinically relevant concentrations (1–3μM), which may be due to the in vivo synergistic effects of PDE-III present in other tissues aside from platelets. Cilostazol does not affect the initial formation of platelet thrombi, but does inhibit the height of thrombi. These results showed a sharp contrast to tirofiban, and address why cilostazol does not significantly prolong bleeding time, despite its strong anti-platelet activity. [Copyright &y& Elsevier]

Summary: Antiplatelet drugs are the cornerstone of treatment for patients with acute coronary syndromes (ACS) who undergo percutaneous coronary intervention. Clopidogrel and aspirin improve long-term clinical outcomes in these patients and have become a standard of care. However, many patients still experience ischemic/thrombotic events, and it appears that insufficient response to both aspirin and clopidogrel contribute to this failure. Clopidogrel is a prodrug that is metabolized in the liver to its active form. It inhibits platelet aggregation induced by adenosine diphosphate (ADP) by irreversibly binding to the ADP purinergic receptor (P2Y12) on the platelet surface. Prasugrel, a novel thienopyridine, exhibits more potent antiplatelet effects with lower interpatient variability and more rapid onsetof activity. All thienopyridines, however, have pharmacological limitations, which have fueled the search for more effective non-thienopyridine P2Y12 inhibitors. Promising results have been reported with ticagrelor, the first oral P2Y12 receptor antagonist with reversible effects. Ticagrelor does not require metabolic activation. In vivo one active metabolite is formed whose potency and pharmacokinetic properties are very similar to those of the parent compound, but it probably plays a minor role in ticagrelor''s antiplatelet effects. Ticagrelor offers more rapid and more pronounced platelet inhibition than other antiplatelet agents. Furthermore, the reversibility of its effects may allow shorter periods of suspension of antiplatelet treatment prior to surgery, reducing the risk of perioperative thrombotic and hemorrhagic events. Preliminary results show a trend toward protection from coronary events and no increased risk for major bleeding compared with clopidogrel. Further investigation is needed, however, to determine the optimal dosage for minimizing bleeding risks and to evaluate its impact on outcomes in various subsets of ACS patients. [Copyright &y& Elsevier]

Currently, many stroke-prone individuals take antithrombotic drugs, which have known antiplatelet properties, to decrease stroke incidence. There is now evidence that this regimen could also reduce stroke severity through neuroprotective, nonplatelet mechanisms that include anti-inflammatory processes. Inflammation was found to play an important role in atherosclerosis/thrombosis development and acute stroke progression. In light of these findings, prevention strategies that target inflammatory mediators are under investigation. A common secondary stroke prevention therapeutic, dipyridamole, has shown promise for reducing stroke recurrence without increasing bleeding. In addition to its antiplatelet ability, dipyridamole has positive effects on vascular endothelium and inflammation. This review explores the effect of dipyridamole during acute stroke, revealing its potential use for improving poststroke clinical outcome. [ABSTRACT FROM AUTHOR]

Summary: Antiplatelet drugs are the cornerstone of treatment for patiens with Acute Coronary Syndromes (ACS) undergoing percutaneous coronary intervention. Clopidogrel and aspirin improve longterm vascular clinical outcomes in these patients and have become a standard of care. However, many patients still experience ischemic/thrombotic events due to potential insufficient platelet inhibition. Prasugrel is a novel third-generation oral thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine. Like the other thienopyridines, prasugrel is a pro-drug requiring hepatic metabolism to its active form to inhibit platelet aggregation induced by Adenosine Diphosphate (ADP) by irreversibly binding to the ADP purinergic receptor (P2Y12) on the platelet surface. Laboratory results with prasugrel support more potent antiplatelet effects, a lower interpatient variability in antiplatelet response, and a reduced time to onset of antiplatelet activity compared with clopidogrel, even when clopidogrel is administered at doses higher than the currently approved 300-mg loading dose and 75-mg/day maintenance dose. These differences may have mainly a pharmacokinetic basis. While the active metabolites of prasugrel and clopidogrel show similar levels of platelet inhibition in vitro, the amount of each active metabolite generated in vivo may be quite different, expecially in some substet of patients (e.g., the so called “CYP2C9 poor metabolizers”). However, it is not yet clear whether these pharmacologic improvements can translate to clinical benefits. The results of the large TRITON-TIMI 38 trial, which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents, demonstrated a significant reduction in ischemic events with prasugrel, although this was associated with a greater risk of bleeding. More studies with prasugrel should determine its optimal dosage regimen to minimize bleeding risks and evaluate its outcomes in ACS in varius subset of patiens. The exact role of prasugrel in the management of coronary heart disease remains to be defined. [Copyright &y& Elsevier]

Aspirin reduces the prevalence of nonfatal myocardial infarction, stroke, and death by 25.0% in high risk group of patients with cardiovascular disease. Previous studies have estimated that about 5.5–56.8% of the population are aspirin resistant. The mechanisms of aspirin resistance (AR) have not been fully understood. We compared the detection methods for AR using traditional platelet aggregometry and VerifyNow system. One hundred and seventy-two coronary artery disease patients who had taken aspirin only or combinations with aspirin and clopidogrel for over 7 days were included. Of the 55 patients with aspirin only, aggregometer detected six AR (10.9%) and VerifyNow identified 10 AR (18.2%) cases. Among 117 patients with combined therapy, none (0.0%) and 10 (8.5%) of AR were detected by aggregometer and VerifyNow, respectively. There were six (3.4%) patients of AR defined by both methods and they all received aspirin monotherapy. Although the correlation between the aggregometry and VerifyNow was low, with defined criteria both methods gave 91.9% agreement to find AR. VerifyNow showed a higher sensitivity to detect AR. Further studies are required to biologically define AR and to alter therapy based on platelet function tests. [ABSTRACT FROM AUTHOR]

Abstract: Internalization of modified low-density lipoprotein (LDL) via macrophage scavenger receptors (e.g. scavenger receptor A and CD36) is thought to play a crucial role in the development of atherosclerotic lesions. Cilostazol, an antiplatelet agent with selective phosphodiesterase 3 inhibitory action, has been reported to ameliorate atherosclerosis in mouse models. However, the effect of cilostazol on modified LDL uptake in macrophages is not known. Thus, we investigated the effect of cilostazol on LDL uptake in mouse peritoneal macrophages (MPM). Cilostazol significantly inhibited oxidized and acetylated LDL uptake in MPM, while cyclic AMP (cAMP)-elevating agents, db-cAMP and other phosphodiesterase 3 or 4 inhibitors, did not inhibit the uptake. Cilostazol did not change cytosolic cAMP levels in MPM, and a protein kinase A (PKA) inhibitor did not influence the inhibitory effects of cilostazol. Cilostazol decreased scavenger receptor A but not CD36 expression. Moreover, cilostazol significantly inhibited foam cell formation, which was represented by an increase in esterified cholesterol content. In conclusion, cilostazol significantly inhibits the uptake of modified LDL and foam cell formation in mouse peritoneal macrophages, and the inhibitory effect of cilostazol can be induced in a cAMP- and PKA-independent manner. [Copyright &y& Elsevier]

Abstract: Problems associated with prosthetic graft replacement are stenosis at the anastomosis site and thrombus formation on the inner surface. Cilostazol is known to have antiplatelet activity and inhibit vascular smooth muscle cell proliferation and neointima thickening. A cilostazol derivative, (-)-6-[3-[3-cyclopropyl-3-[(1R,2R)-2-hydroxycyclohexyl]ureido]-propoxy]-2-(1H)-quinolinone (K-134), has more potent anti-platelet activity and anti-neointimal thickening activity than cilostazol in the in-vitro platelet aggregation and in-vivo anti-hyperplastic activity assay. The aim of this study was to investigate effects of cilostazol and K-134 on thrombus formation and neointimal thickening at the site of prosthetic graft replacement. Beagle dogs underwent infrarenal abdominal aortic resection with straight Dacron graft replacement, which were allocated to the control, cilostazol, and K-134 groups. Two dogs were dead without confirming the cause of death. After 6 months, all dogs were necropsied. All prosthetic grafts were patent in each group. Ratios of red thrombus to prosthetic graft area were 0.3±6.4%, and 3.3±4.5% in the cilostazol and K-134 groups, respectively, which were significant different from that in the control group (24.4±16.8%). However, no clear difference was seen among the 3 groups with respect to neointimal thickness (control group, 0.70±0.13 mm; cilostazol group, 0.59±0.14 mm; K-134 group, 0.67±0.14 mm). Cilostazol and K-134 significantly inhibited thrombus formation on the inner surface of the prosthetic graft at 6 months after graft replacement. Neointimal thickening on the inner surface was slight even in control-group animals, and the effects of cilostazol and K-134 on such thickening were unclear. [Copyright &y& Elsevier]

Recently we showed that the P2Y1 receptor coupled to calcium mobilization is necessary to initiate ADP-induced human platelet aggregation. Since the thienopyridine compound clopidogrel specifically inhibits ADP-induced platelet aggregation, it was of interest to determine whether the P2Y1 receptor was the target of this drug. Therefore we studied the effects of clopidogrel and of the two specific P2Y1 antagonists A2P5P and A3P5P on ADP-induced platelet events in rats. Although clopidogrel treatment (50 mg/kg) greatly reduced platelet aggregation in response to ADP as compared to untreated platelets, some residual aggregation was still detectable. In contrast, A2P5P and A3P5P totally abolished ADP-induced shape change and aggregation in platelets from both control and clopidogrel-treated rats. A2P5P and A3P5P (100 μM) totally inhibited the [Ca2+]i rise induced by ADP (0.1 μM) in control and clopidogrel-treated platelets, whereas clopidogrel treatment had no effect. Conversely, the inhibition of adenylyl cyclase induced by ADP (5 μM) was completely blocked by clopidogrel but not modified by A2P5P or A3P5P (100 μM). A3P5P (1 mM) reduced the number of [33P]2MeSADP binding sites on control rat platelets from 907 ± 50 to 611 ± 25 per platelet. After clopidogrel treatment, binding of [33P]2MeSADP decreased to 505 ± 68 sites per platelet and further decreased to 55 ± 12 sites in the presence of A3P5P (1 mM). In summary, these results demonstrate that the platelet P2Y1 receptor responsible for the initiation of aggregation in response to ADP is not the target of clopidogrel. Platelets may express another, as yet unidentified, P2Y receptor, specifically coupled to the inhibition of adenylyl cyclase and necessary to induce full platelet aggregation, which could be the target of this drug. [ABSTRACT FROM AUTHOR]

We hypothesized that administration of cilostazol may clarify the occult atrial fibrillation (AF) during hospitalization in mild stroke patients, who has no history of AF. From our prospective non-cardioembolic stroke study, randomized to dual antiplatelet therapy using cilostazol and aspirin or aspirin alone trial (ADS), data on the presence or absence of AF were retrospectively analyzed. In the ADS, during hospitalization, as a routine examination, presence of AF was investigated using electrocardiogram (ECG), ECG monitoring and Holter ECG. Multivariate regression analysis was conducted to evaluate the independent parameters related to the AF. Clinical outcome at 3 months was evaluated using modified Rankin Scale (mRS) score. Data on 1194 patients (793 [66%] men; median age [interquartile range] of 69 [61–77] years, National Institutes of Health Stroke Scale score 2 [1–4], onset-to-admission 10.8 [4.7–20.5] hours) were retrospectively analyzed. AF was newly detected in 41 (3%) patients (3 by ECG, 21 by the ECG monitoring and 17 by the Holter ECG) during hospitalization. Patients treated with combined cilostazol and aspirin therapy frequently had the AF than those took aspirin alone (5% vs. 2%, p =.007). Multivariate regression analysis showed that cilostazol administration was one of the independent factors for new-AF (odds ratio 2.672, 95%CI: 1.205–5.927, p =.016). The frequency of mRS 0-1 was 68% in the new-AF group and 67% in the non-AF group (p = 1.000). Cilostazol therapy may increase the detectability of AF in acute non-cardioembolic stroke, though the new-AF was not related to clinical outcome at 3 months. • Cilostazol is often used for mild stroke patients without atrial fibrillation (AF). • Cilostazol stimulates vessels and cardiac system. • Retrospective analysis focused on 1194 patients without AF on admission. • Cilostazol administration was independently related to the new-AF detection. • Cilostazol may increase the detectability of AF in acute stroke patients. [ABSTRACT FROM AUTHOR]

In the field of antithrombotics, precision medicine is of particular interest, as it may lower the incidence of potentially life-threatening side effects. Indeed, antiplatelet drugs such as P2Y12 inhibitors are one of the most common causes of emergency admissions for drug-related adverse events. The last ten years have seen a continuous debate on whether platelet function tests (PFTs) should be used to tailor antiplatelet drugs to cardiovascular patients. Large-scale randomized studies investigating the escalation of antiplatelet therapies according to the results of PFTs were mostly negative. Potent P2Y12 inhibitors are recommended as a first-line treatment in acute coronary syndrome patients, bringing the bleeding risk at the forefront. De-escalation from prasugrel or ticagrelor to clopidogrel is now considered, with or without the use of a PFT. This review covers recent advances in escalation and de-escalation strategies based on PFTs in various clinical settings. It also describes the main features of the most popular platelet function tests as well as the potential added value of genetic testing. Finally, we detail practical suggestions on how PFTs could be used in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Extensive research has reported that extracellular ADP in the tumour microenvironment can stimulate platelets through interaction with the platelet receptor P2Y12. In turn, activated platelets release biological factors supporting cancer progression. Experimental data suggest that the tumour microenvironment components, of which platelets are integral, can promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Thus, overcoming chemoresistance requires combining multiple inhibitors that simultaneously target intrinsic pathways in cancer cells and extrinsic factors related to the tumour microenvironment. We aimed to determine whether ticagrelor, an inhibitor of the ADP–P2Y12 axis and a well-known antiplatelet drug, could be a therapeutic option for PDAC. Methods: We investigated a functional P2Y12 receptor and its downstream signalling in a panel of PDAC cell lines and non-cancer pancreatic cells termed hTERT-HPNE. We tested the synergistic effect of ticagrelor, a P2Y12 inhibitor, in combination with chemotherapeutic drugs (gemcitabine, paclitaxel and cisplatin), in vitro and in vivo. Results: Knockdown studies revealed that P2Y12 contributed to epidermal growth factor receptor (EGFR) activation and the expression of SLUG and ZEB1, which are transcriptional factors implicated in metastasis and chemoresistance. Studies using genetic and pharmacological inhibitors showed that the P2Y12–EGFR crosstalk enhanced cancer cell proliferation. Inhibition of P2Y12 signalling significantly reduced EGF-dependent AKT activation and promoted the anticancer activity of anti-EGFR treatment. Importantly, ticagrelor significantly decreased the proliferative capacity of cancer but not normal pancreatic cells. In vitro, synergism was observed when ticagrelor was combined with several chemodrugs. In vivo, a combination of ticagrelor with gemcitabine significantly reduced tumour growth, whereas gemcitabine or ticagrelor alone had a minimal effect. Conclusions: These findings uncover a novel effect and mechanism of action of the antiplatelet drug ticagrelor in PDAC cells and suggest a multi-functional role for ADP-P2Y12 signalling in the tumour microenvironment. [ABSTRACT FROM AUTHOR]

Abstract: Background context: There have been some reports describing hematoma in the thoracic and lumbar ligamentum flavum, but there have been only three reports of hematoma in the cervical ligamentum flavum. Purpose: We describe another case of the ligamentum flavum hematoma in the cervical spine with a different feature of occurrence that required surgical treatment. Study design: Case report. Patient sample: Patient with ligamentum flavum hematoma in the cervical spine. Outcome measures: Preoperative magnetic resonance imaging and pathologic finding from operative specimen confirmed the diagnosis. Methods: A 69-year-old man insidiously presented with pain in his left upper arm and difficulty in left shoulder abduction. Neurologic examination demonstrated a cervical myelopathy with diffuse muscle weakness of left upper extremity and sensory disturbance. Imaging studies revealed a mass of high intense on T1-weighted images and isointense on T2-weighted images posterior to the dura at C4 lower end level. The patient underwent C4–C5 hemilaminectomy and the removal of the mass. The mass existed within the ligamentum flavum and was connected toward the pedicle like the beads of a rosary. Results: Histopathologic examination of the surgical specimen showed that the hematoma was present within the ligamentum flavum and contained macrophages that had phagocytosed red blood cells and hemosiderin. After surgery, the patients'' symptoms immediately improved, and no recurrence was observed at 2 years postoperatively. Conclusions: We reported a very rare case of hematoma in the ligamentum flavum of the cervical spine that required surgery. Because the patient was without the history of trauma, it was suggested that the use of antiplatelet drugs was responsible for the occurrence of the disease. [Copyright &y& Elsevier]