Antiplatelet Effects Research Articles

Omega-3 Fatty Acids Reduce Remnant-like Lipoprotein Cholesterol and Improve the Ankle-Brachial Index of Hemodialysis Patients with Dyslipidemia: A Pilot Study.

Background and Objectives: Omega-3 fatty acids have potent lipid-lowering and antiplatelet effects; however, randomized controlled trials have yet to examine the effect of high-dose omega-3 fatty acid administration on peripheral artery disease (PAD) in hemodialysis patients with dyslipidemia. Therefore, this study aimed to evaluate the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the ankle-brachial index (ABI) and remnant-like lipoprotein cholesterol (RLP-C) levels, which are indicators of PAD severity. Materials and Methods: Thirty-eight participants (mean age: 73.6 ± 12.7 years) were randomly assigned using stratified block randomization to either conventional therapy alone or conventional therapy supplemented with high-dose EPA/DHA (EPA: 1860 mg; DHA: 1500 mg) for a three-month intervention period. Patients in the conventional therapy alone group who opted to continue were provided with a low-dose EPA/DHA regimen (EPA: 930 mg; DHA: 750 mg) for an additional three months. The baseline and 3-month values for RLP-C, an atherogenic lipid parameter, and the ABI were recorded. Results: The results of the 3-month assessments revealed that the mean RLP-C changes were -3.25 ± 3.15 mg/dL and 0.44 ± 2.53 mg/dL in the EPA/DHA and control groups, respectively (p < 0.001), whereas the changes in the mean ABI values were 0.07 ± 0.11 and -0.02 ± 0.09 in the EPA/DHA and control groups, respectively (p = 0.007). In the EPA/DHA group, a significant negative correlation was found between the changes in RLP-C levels and the ABI (r = -0.475, p = 0.04). Additionally, the change in the RLP-C levels independently influenced the change in the ABI in the EPA/DHA group, even after adjusting for age, sex, and statin use (p = 0.042). Conclusions: Add-on EPA/DHA treatment improved the effectiveness of conventional therapy (such as statin treatment) for improving the ABI in hemodialysis patients with dyslipidemia by lowering RLP-C levels. Therefore, clinicians involved in dialysis should focus on RLP-C when considering residual cardiovascular disease risk in hemodialysis patients and should consider screening patients with elevated levels.

Analysis of Platelet Function Testing in Children Receiving Aspirin for Antiplatelet Effects.

Aspirin (ASA) remains the most common antiplatelet agent used in children. VerifyNow Aspirin Test® (VN) assesses platelet response to ASA, with therapeutic effect defined by the manufacturer as ≤ 549 aspirin reaction units (ARU). Single-center, observational, analysis of 195 children (< 18years-old) who underwent first VN between 2015 and 2020. Primary outcome was proportion of patients with ASA biochemical resistance (> 549 ARU). Secondary outcomes included incidence of new clinical thrombotic and bleeding events during ≤ 6months from VN in those who received ASA monotherapy (n = 113). Median age was 1.8years. Common indications for ASA included cardiac anomalies or dysfunction (74.8%) and ischemic stroke (22.6%). Median ASA dose before VN was 4.6mg/kg/day. Mean VN was 471 ARU. ASA biochemical resistance was detected in 14.4% (n = 28). Of 113 patients receiving ASA monotherapy, 14 (12.4%) had a thrombotic event and 2 (1.8%) had a bleeding event. Mean VN was significantly higher at initial testing in patients experiencing thrombotic event compared to those without thrombosis (516 vs 465 ARU, [95% CI: 9.8, 92.2], p = 0.02). Multivariable analysis identified initial VN ASA result ≥ 500 ARU at initial testing as the only significant independent risk factor for thrombosis (p < 0.01). VN testing identifies ASA biochemical resistance in 14.4% of children. VN ASA ≥ 500 ARU rather than ≥ 550 ARU at initial testing was independently associated with increased odds of thrombosis. Designated cut-off of 550 ARU for detecting platelet dysfunction by ASA may need reconsideration in children.

Oil from Mullet Roe Byproducts: Effect of Oil Extraction Method on Human Erythrocytes and Platelets.

Background: The valorization of byproducts to obtain high nutritional value foods is of utmost importance for our planet where the population is booming. Among these products are oils rich in ω-3 fatty acids produced from fishery byproducts. Recently, mullet roe oil from roe byproducts was produced that was rich in the ω-3 fatty acids eicosatetraenoic acid (EPA) and docosahexaenoic acid (DHA). Oils are customarily characterized for their composition and degree of oxidation but little is known of their biological effects, especially the effect of the extraction method. Methods: The purpose of this study was to evaluate the effects of freshly extracted mullet roe oil from mullet roe byproducts and the effect of the extraction method on human red blood cells (hRBCs) and platelets. To this end, the hemocompatibility (cytotoxicity), oxidative effects, and erythrocyte membrane changes were examined after 1 and 24 h of incubation. Antiplatelet effects were also assessed in vitro. Results: The expeller press oil extraction method and alcalase-assisted extraction produced the most biocompatible oils, as shown by hemocompatibility measurements and the absence of erythrocyte membrane alterations. Solvent extracts and protease-assisted extraction oils resulted in the rupture of red blood cells at different examined dilutions, creating hemolysis. Conclusions: It seems that the proper functioning of oil-erythrocyte interactions cannot be explained solely by ROS. Further investigations combining chemical analysis with oil-cell interactions could be used as an input to design high nutritional value oils using green extraction technologies. All samples exhibited promising antiplatelet and antiblood clotting effects in vitro.

Periprocedural antiplatelet medication assessed by VerifyNow for neuroendovascular treatment: Comparison of prasugrel with clopidogrel

Objective 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. Methods 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 &lt; 208 as the optimal range. Perioperative complications within seven days of surgery were also analyzed. Results 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 &lt; 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 &gt; 208 than in those with PRU &lt; 208 (12.5% vs. 3.8%, p = 0.044). The hemorrhagic complication rate was not significantly different between the PRU &lt; 95 and 95≦PRU groups (8.4% vs. 3.2%, p = 0.224). Conclusions 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 &lt; PRU group.

Evaluation of the antiplatelet effect of generic ticagrelor 90 mg (ticaspan ® ) alone and in combination with aspirin 75 mg as compared to ticagrelor (innovator): An in vitro study.

To evaluate an in vitro antiplatelet effect of generic ticagrelor 90 mg (ticaspan) alone and in combination with aspirin 75 mg as compared to the innovator formulation of ticagrelor alone and in combination with aspirin among healthy Indian volunteers. 18 volunteers were enrolled and platelet viability was tested using lactate dehydrogenase (LDH) assay in six of 18 volunteers. In 12 volunteers, maximum platelet aggregation (MPA) and percentage inhibition of platelet aggregation (PI) were assessed using a platelet aggregometer in six study groups. There was no significant increase in LDH levels when platelets were incubated with an innovator or generic drug alone and in combination with aspirin as compared to the dimethyl sulfoxide [DMSO] group. All five study groups showed a significant reduction in the MPA values compared to the DMSO group ( P < 0.01). The extent of decrease in MPA observed with the generic drug was not significantly different from the innovator drug ( P = 0.325). Similarly, the MPA observed with the two combination groups did not differ from each other ( P = 1.000), but it was significantly different from the MPA observed with aspirin ( P = 0.039, each). The PI of platelet aggregation was significantly more in four study groups [generic drug alone; innovator alone; generic drug + aspirin; and innovator drug + aspirin] ( P < 0.01) as compared to the aspirin group. The generic ticagrelor and its combination with aspirin demonstrated an antiplatelet effect equivalent to the innovator drug and its combination with aspirin.

Exploring the Therapeutic Potential: Antiplatelet and Antioxidant Activities of Some Medicinal Plants in Morocco

Background:: Thrombotic events and oxidative stress are major complications of certain ischemic disorders. The fight against these complications requires very intense research to develop new therapeutic agents of natural origin. Objective:: The general objective of this work is the scientific valorization of five medicinal plants: Rhus pentaphylla, Zizyphus lotus, Ammodaucus leucotrichus, Inula viscosa, and Cinnamomum zeylanicum by exploring their effects on rat platelet aggregation, antioxidant potential and determining their phytochemical composition. Methodology:: The aggregation test was monitored by stimulating isolated washed platelets suspension in the absence and presence of extracts. The antioxidant activity was conducted in vitro according to three methods: DPPH free radical scavenging activity, β-carotene bleaching test, and ferric reducing antioxidant power test. The quantitative determination of total polyphenols and flavonoids are determined respectively according to the Folin-Ciocalteu method and the colorimetric method with aluminum chloride. Results:: The results obtained show that the aqueous extract of the fruits of Rhus pentaphylla and the aerial part of Inula viscosa, as well as the stalk peel of Cinnamomum zeylanicum, significantly (p˂0.001) inhibit thrombin-platelet aggregation, while the other plant extracts have a slightly, but significant effect. These extracts exert a remarkable antioxidant activity with the three methods used. But, their IC50 values are still higher than those of the antioxidant references (ascorbic acid and butyl hydroxyanisole). Qualitative phytochemical analysis revealed the presence of secondary metabolites with varying contents. Additionally, the results of quantitative phytochemical analysis showed that the aqueous extracts of the leaves of Rhus pentaphylla and the aerial part of Inula viscosa contain the highest amount of polyphenols and flavonoids. These secondary metabolites are also present in the other extracts but in smaller quantities. Conclusion:: These results could contribute to the validation of the medical use of these extracts that exert an antiplatelet effect to treat hemostatic and thrombotic disorders.

Ginsenosides: An overview of its antiplatelet effects and its underlying mechanisms

GINSENOSIDES, the principal constituent of plants from genus Panax, have been indicated in multitudinous of ailments by the Homos sapiens, for more than 2 millennia. Mostly and notably the ginsenosides, the mainstay of Chinese herbal system of medication, are harnessed for multifarious disorders viz. Neurodegenerative diseases, Diabetes mellitus, Cardiovascular abnormalities, Septic shock, inflammatory disorders, Obesity and most striking of all owing to the prevalent circumstances have to potential to manage, even treat COVID-19, albeit empirically. Whereas, considering the plant itself, it strikes to the researcher as perennial although, with significantly slow progress. The spectrum of the review encompasses the functional reach of the ginsenosides with special emphasis on the antiplatelet therapeutics, in conjunction with the notoriety and the prospect of the compounds in multitude of disorders. However, the mechanism on which the edifice, of the antithrombotic efficiency is contingent, is expressed with keen interest. Ultimately, the root or its extract, is evidenced to be sufficiently effective in curbing the foresaid ailments whether authenticated by systematic review, clinical trials, mechanistic patterns and animal investigations. Overall, the herb shows immense potential to be packaged into a unit dosage form and be brought in the prevalent market especially as an antithrombotic agent.

Statins Effects on Blood Clotting: A Review.

Statins are powerful lipid-lowering drugs that inhibit cholesterol biosynthesis via downregulation of hydroxymethylglutaryl coenzyme-A reductase, which are largely used in patients with or at risk of cardiovascular disease. Available data on thromboembolic disease include primary and secondary prevention as well as bleeding and mortality rates in statin users during anticoagulation for VTE. Experimental studies indicate that statins alter blood clotting at various levels. Statins produce anticoagulant effects via downregulation of tissue factor expression and enhanced endothelial thrombomodulin expression resulting in reduced thrombin generation. Statins impair fibrinogen cleavage and reduce thrombin generation. A reduction of factor V and factor XIII activation has been observed in patients treated with statins. It is postulated that the mechanisms involved are downregulation of factor V and activated factor V, modulation of the protein C pathway and alteration of the tissue factor pathway inhibitor. Clinical and experimental studies have shown that statins exert antiplatelet effects through early and delayed inhibition of platelet activation, adhesion and aggregation. It has been postulated that statin-induced anticoagulant effects can explain, at least partially, a reduction in primary and secondary VTE and death. Evidence supporting the use of statins for prevention of arterial thrombosis-related cardiovascular events is robust, but their role in VTE remains to be further elucidated. In this review, we present biological evidence and experimental data supporting the ability of statins to directly interfere with the clotting system.

Flavonol and A-type procyanidin-rich extracts of Prunus spinosa L. flower exhibit anticoagulant activity through direct thrombin inhibition, but do not affect platelet aggregation in vitro

Background: Blackthorn flower (Prunus spinosa L.) is a traditional herbal remedy recommended for treating cardiovascular diseases (CVDs).Aim: This in vitro study investigates the effects of flavonol and A-type procyanidin-rich blackthorn flower extracts on the hemostatic system, including the blood plasma coagulation cascade and platelet aggregation.Methods: Six distinct extracts, characterized through various techniques, including LC-MS/MS, were assessed at in vivo-relevant levels (1–50 μg/mL) for their antithrombotic activity. The thrombin, prothrombin, and activated partial thromboplastin times were measured. Additionally, the thrombin enzymatic activity was tested using the chromogenic substrate S-2238 and fibrinogen as the physiological substrate of the enzyme. To gain insights into the mechanism of action, the interactions between the primary extracts’ constituents, their potential metabolites, and thrombin were examined in silico. The computational analyses were complemented by in vitro experiments and circular dichroism spectroscopy. The platelet aggregation in human platelet-rich plasma was assessed after ADP or collagen stimulation. Furthermore, the extracts’ biocompatibility was tested on human peripheral blood mononuclear cells (PBMCs) and red blood cells (RBCs).Results: The extracts slightly prolonged the prothrombin and thrombin times and effectively inhibited the thrombin’s enzymatic activity, reducing its amidolytic and proteolytic functions at 50 μg/mL by 91.2% and 74.8%, respectively. In silico molecular docking demonstrated a strong binding affinity of the examined polyphenols and their metabolites to thrombin. Most analytes bound exclusively within the enzyme active site; however, afzelin, kaempferitrin, and procyanidin A2 revealed the affinity to additional binding sites, including exosite I. The structure-activity relationship of flavonols as thrombin inhibitors was studied in vitro. Circular dichroism spectroscopy confirmed that the interactions between thrombin and the compounds (even at 1 μg/mL) induce alterations within the α-helices’ secondary structure, resulting in noticeable changes in the enzyme’s CD spectrum. On the other hand, the extracts did not influence platelet aggregation. Eventually, their cellular biocompatibility with PBMCs and RBCs was confirmed.Conclusion: The extracts directly inhibit thrombin, a critical serine protease in hemostasis and a prime anticoagulant drug target, and do not exhibit antiplatelet effects. This study enhances the knowledge of the biological activity of blackthorn flowers and supports their traditional use in CVDs.

Synthesis and bioevaluation of Scutellarein-Tertramethylpyrazine hybrid molecules for the treatment of ischemic stroke

Ischemic stroke caused by insufficient blood supply to the brain may produce a sequence of cascade reactions, leading to oxidative stress and ultimately inducing nerve cell damage. Therefore, hybrid molecules with multiple therapeutic effects have irreplaceable advantages for the treatment of ischemic stroke. Based on the previous works, two types of Scutellarein and Tertramethylpyrazine hybrid molecules were designed and synthesized according to the PepT 1-based design. After systematic research, all synthesized hybrid molecules exhibited more excellent neuroprotective effect and antiplatelet activity compared to the original drugs. Among them, the selected compound 1e with superior neuroprotective and antiplatelet effects could significantly enhance the permeability on the Caco-2 monolayer membrane and inhibit the Gly-Sar uptake on Caco-2 cells. Meanwhile, the result of intestinal perfusion has also confirmed that the absorption of the selected compound 1e is indeed increased. Further, the selected compound 1e significantly reduce the cerebral infarction volume of middle cerebral artery occlusion/reperfusion rats. Especially, the cerebral infarction volume of the high-dose 1e group reduced to one fourth of the model group. Meanwhile, results of hematoxylin-eosin staining also indicated that the damage in the hippocampus CA1 region was significantly alleviated after treatment with the compound 1e. Accordingly, molecular hybridization strategy is one of the simple and feasible ways to improve the therapeutic effect of single targeted drug.

In vitro comparison of platelet aggregation between zalunfiban and selatogrel in healthy donors

Abstract Background Two subcutaneously injected antiplatelet drugs, zalunfiban and selatogrel, are under development for prehospital administration for STEMI and (N)STEMI, respectively. Zalunfiban is a glycoprotein IIb/IIIa inhibitor that produces high-grade inhibition of platelet aggregation induced by ADP or a thrombin receptor activating peptide (TRAP) within 15 minutes. Selatogrel is a P2Y12 inhibitor that produces high-grade inhibition of platelet aggregation initiated by ADP within 15 minutes. We have studied the relative potencies of the drugs at levels achievable in vivo in inhibiting platelet aggregation. Since trisodium citrate (TSC) has been reported to enhance the antiplatelet effect of zalunfiban and inhibit the antiplatelet effect off selatogrel, aggregation studies were performed with both blood anticoagulated with TSC and the non-chelating anticoagulant PPACK. Whereas both ADP and thrombin are present at the site of vascular injury within seconds, we tested the effects of both ADP and TRAP. Purpose To compare directly the effects of zalunfiban and selatogrel on ADP- and TRAP-induced platelet aggregation. Methods Light transmission platelet aggregometry was performed within 4 hours of blood collection (BioData PAP-8E). Whole blood from healthy donors not taking aspirin (N=10) was anticoagulated with 3.2% TSC and 100 μM PPACK. Platelet-rich plasma (PRP) was prepared and adjusted to a platelet count of 250,000/µl. Three clinically relevant incremental concentrations of zalunfiban and selatogrel were added to PRP and platelet aggregation was initiated with 20 μM ADP or 20 μM TRAP. Tracings were recorded for at least 10 minutes after agonist addition. Platelet aggregation was quantified based on the instrument’s measurement of the primary slope (PrSl) of aggregation, which is a measure of the change in light transmission per unit time sustained over at least a 15 second period. Results In TSC-anticoagulated PRP, zalunfiban was more effective in inhibiting the PrSl of both ADP- and TRAP-induced platelet aggregation at all drug concentrations [Figure 1, panel A and B]. In PPACK-anticoagulated PRP, selatogrel showed greater inhibition of ADP-induced platelet aggregation at the lowest concentration tested, similar inhibition at the intermediate concentration, and slightly less inhibition at the highest doses. In sharp contrast, with TRAP-induced aggregation, zalunfiban demonstrated dose-related inhibition, reaching greater than 80% inhibition at the highest dose, whereas selatogrel produced less than 20% inhibition at all three doses. Conclusion Selatogrel is a potent inhibitor of ADP-induced platelet aggregation, but has low impact on TRAP-induced platelet aggregation, whereas zalunfiban is a potent inhibitor of both ADP and TRAP-induced platelet aggregation. The difference between the drugs needs to be considered in light of the known generation of thrombin at the site of vascular injury within seconds.Comparison of Platelet Inhibition

Risks and benefits of antiplatelet therapy in patients with abdominal aortic aneurysm without symptomatic atherosclerotic disease: a nationwide cohort study

Abstract Background Patients with abdominal aortic aneurysm (AAA) suffer a high risk of ischemic events associated with concomitant atherosclerotic cardiovascular disease, and current clinical practice guidelines recommend antiplatelet therapies to mitigate this risk. However, in patients with AAA and no symptomatic atherosclerosis, the benefit of antiplatelet is sparsely investigated. Purpose To assess the effectiveness of antiplatelets vs no antiplatelets on the risk of ischemic events (composite of myocardial infarction and ischemic stroke) and bleeding in individuals with AAA who had no concomitant atherosclerotic vascular disease. Methods We designed a target trial to compare outcomes among treatment initiators and non-initiators and emulated the trial contingent on patient eligibility at time of inclusion, utilizing Danish nationwide observational data from January 2010 through August 2021. Confounding was handled by means of inverse probability treatment weighting based on the propensity score. The emulated sequential trial results for all possible trial months were pooled by means of pooled logistic regression models to estimate the intention-to-treat average treatment effects, and the 5-year associated treatment differences were expressed as hazard ratio (HR) with 95% confidence intervals (CI) and estimated event-free survival. Results A total of 6,344 patients provided 131,047 trial participants: 3,363 of these were new initiators of antiplatelet therapy, while 127,684 were non-initiators. During a median follow-up of 24 months, 173 and 369 ischemic events occurred among initiators and non-initiators, respectively. The corresponding HR of 0.91 (CI 95% 0.73 to 1.17) and an estimated absolute event-free survival difference of -0.6% (Figure 1). For bleeding, the HR was 1.26 (CI 0.97 to 1.58) and the event-free survival difference was 1.0%. Conclusion This target trial emulation, using nationwide observational data on all patients with AAA and no record of symptomatic atherosclerotic disease, did not find evidence of antiplatelets to lower the risk of ischemic events, but also no evidence of substantial higher bleeding risk. The observed differences between the treatment groups were minimal, suggesting limited clinically relevance of this treatment.ischemia- and bleeding free survival

Antiplatelet effect of acetylsalicylic acid in patients early after cardiac valve surgery: comparative investigation of the impairment of platelet inhibition by dipyrone versus acetaminophen

Abstract Background Low-dose acetylsalicylic acid (ASA) is recommended in current guidelines for a period of 3 months after surgical implantation of a bioprosthesis in aortic position or after surgical repair of the mitral valve. Dipyrone (D; metamizole) and acetaminophen (A; paracetamol) are frequently used non-opioid analgesics after surgery. The active metabolite of dipyrone (4-methylaminoantipyrine) is a reversible inhibitor of cyclooxygenase-1 and an interaction with the antiplatelet effect of ASA in more than 50 % of patients has been reported. Material and methods We enrolled 162 patients scheduled for cardiac surgery in this prospective investigator-initiated clinical study. Patients were randomized at day 1 after surgery to either 4 x 1g dipyrone iv/day or 4 x 1g acetaminophen iv/day. All patients were on ASA 100 mg daily (200 mg at day 1). The primary endpoint was the proportion of patients with adequate antiplatelet response to ASA assessed via determination of thromboxane B2 in platelet rich plasma after stimulation with arachidonic acid (AA) at day 4/5 after surgery (cutpoint ≤209.8 ng/ml thromboxane B2). Key secondary endpoints comprised platelet reactivity assessed by light transmission aggregometry [LTA] and by multiple electrode impedance aggregometry [MEIA]. Results 15 patients dropped out of the study. Thus, data from 71 patients randomized to dipyrone and 76 patients randomized to acetaminophen were available for data analysis. Patients had a mean age of 66.5±7.6 years and 97 were male and 50 female. Aortic valve was replaced in 92 patients, 54 underwent mitral valve reconstruction and combined surgery was performed in a single patient. The primary endpoint analyzed at day 4/5 after surgery is shown in the Figure. The proportion of non-responders was 12.5% (D) and 3.0% (A), respectively. Platelet reactivity at day 4/5 after surgery was assessed after stimulation with arachidonic acid by LTA or MEIA. No statistically significant difference between the treatment strata was determined in both assays: Maximum aggregation in LTA was 5.0% (median; 95% confidence interval [95% CI]: 4.0 - 8.0%) in D+ASA and 6.0% (95% CI: 5.0 - 11.0%) in A+ASA (p=0.528) and MEIA AUC was 345.5 AU*min (95% CI: 268.0 - 419.0) in D+ASA and 276.5 AU*min (95% CI: 241.0 - 330.0) in A+ASA (p=0.098). Plasma concentrations of MAA in patients treated with dipyrone were higher in patients identified as responders to ASA (86.6 µM; 95% CI: 67.9 - 102.4 µM) compared to non-responders (31.0 µM; 95% CI: 2.9 – 146.7 µM; p=0.0147). Summary and conclusion The proportion of non-responders to ASA is higher in patients treated with dipyrone compared to acetaminophen. The proportion of non-responders in the dipyrone-treated group in our study is substantially lower than reported in previous studies. High plasma concentrations of MAA in responders may contribute to enhanced inhibition of COX-1 in patients treated with dipyrone.

Interactions between aspirin and ticagrelor during experimental human endotoxaemia

Abstract Introduction Dual antiplatelet therapy (DAPT) with aspirin 75-100mg once daily (OD) and the P2Y12 inhibitor ticagrelor is a standard treatment for acute coronary syndromes. De-escalating DAPT to ticagrelor monotherapy reduces bleeding risk yet appears to have minimal ischaemic penalty in most groups. The reason for this is unclear. P2Y12 inhibition can inhibit inflammatory processes relevant to atherothrombosis but aspirin may hypothetically counter these via platelet PGE2 inhibition. We studied the regimen-dependent effects of aspirin +/- ticagrelor in a human model of endotoxaemia. Endotoxin activates toll-like receptor 4, a key damage receptor in atherogenesis. Methods 72 healthy volunteers were randomised to receive either no aspirin or aspirin 20mg twice daily (BD), 75mg OD or 300mg OD for 10 days +/- a loading dose of ticagrelor on the last day prior to receiving intravenous endotoxin administration (2ng/kg). Blood was collected at 9 timepoints from 1h pre to 6h post endotoxin. Key cytokines and prostanoids in the blood/urine were measured by ELISA, platelet function by light transmittance aggregometry and platelet-leukocyte interaction by flow cytometry. Bleeding time was measured pre and 3h post endotoxin. After &amp;gt;5 weeks, in a 2nd period they received the same dose of aspirin as the 1st but received ticagrelor if they had not already, and vice versa, undergoing a 2nd endotoxin challenge at the end of the period. The primary endpoint was plasma tumour necrosis factor (TNF)-α. Results 72 participants were randomised (median 22.5yrs [range 18-59], 6F:66M). A total of 128 endotoxin challenges were performed. Endotoxaemia was associated with flu-like symptoms, pyrexia, tachycardia and relative hypotension but was safe. In those not receiving aspirin, plasma TNF-α was significantly lower when receiving ticagrelor vs. no ticagrelor, but in those receiving any dose of aspirin the significant effect of ticagrelor was abolished (Fig 1). All doses of aspirin fully suppressed arachidonic acid-induced PA with or without ticagrelor despite the thromboinflammatory stimulus of endotoxaemia (Fig 2A), and significantly augmented the inhibitory effect of ticagrelor on collagen-induced PA (2B). Aspirin 75mg OD and 300mg OD, but not 20mg BD, significantly prolonged bleeding time from baseline (2C). Ticagrelor significantly prolonged bleeding time in combination with any dose of aspirin or no aspirin. Aspirin dose-dependently inhibited PGE2 release. Conclusions All doses of aspirin tested prevented the ability of ticagrelor to significantly inhibit cytokine release during experimental endotoxaemia. Aspirin 20mg BD may offer improved bleeding risk with maintained antiplatelet effect compared to standard regimens. Where ticagrelor monotherapy is an option, dropping aspirin may allow ticagrelor to exert greater beneficial effect on inflammatory pathways relevant to atherothrombosis, potentially reducing ischaemic risk whilst also reducing bleeding risk.Figure 1Figure 2

Intensity of dual antiplatelet therapy based on thrombotic and bleeding risks after coronary stenting

Abstract Background/Introduction High thrombotic risk (HTR) features are associated with higher ischemic rate, which may be mitigated by potent antiplatelet therapy. However, concomitant high bleeding risk (HBR) may be present, making it unclear whether the intensity of antiplatelet therapy should be prioritized. Purpose This study investigated the prognostic implications of HTR and HBR strata according to intensity of antiplatelet therapy (indicated by platelet reactivity) after coronary stenting. Methods HTR was defined as having at least one of the three risk factors: 1) index presentation with acute coronary syndrome; 2) complex coronary artery disease and stenting; and 3) guideline-directed clinical ischemic risk factors. HBR was determined according to presence of Academic Research Consortium (ARC)-HBR criteria. In addition, high platelet reactivity (HPR) was decided depending on the level of platelet reactivity (&amp;gt; 208 P2Y12 reaction unit measured by VerifyNow assay). Results Among 4,550 patients, HTR features were observed in 3,973 patients (87.3%) and 1,451 (31.9%) met the ARC-HBR criteria. HPR phenotype (n=2563, 56.3%) significantly increased the risk of 4-year ischemic events (adjusted hazard ratio [HRadj]: 1.40; 95% confidence interval [CI]: 1.15-1.70; P=0.001). Among patients who met the ARC-HBR criteria, HPR was not associated with the rate of ischemic events, regardless of HTR features. In cases of non-HBR patients, HPR phenotype increased ischemic events only in patients with HTR feature(s), which risk proportionally increased according to the number of HTR features (HRadj: 0.67, 1.47 and 1.58; 95% CI: 0.22-2.08, 0.94-2.29 and 1.09-2.28 in 0 [9.2%], 1 [31.2%] and ≥2 [27.7%] HTR features). In HBR patients, the risk of major bleeding was not increased by the level of antiplatelet effect. Conclusion HPR phenotype was significantly associated with the risk of ischemic events after coronary stenting, which proportionally increased according to the number of HTR features only if the ARC-HBR criteria were not present. These observations suggested that when concordant, bleeding risk, more than ischemic risk, should inform decision-making on the intensity of antiplatelet therapy.KM curve and HR forest plot for MACCEKM curve and HR forest plot for NACE

Targeting memory loss with aspirin, a molecular mechanism perspective for future therapeutic approaches.

Acetylsalicylic acid (ASA), also known as aspirin, was discovered in 1897 as an acetylated form of salicylate. It has been widely used for its anti-inflammatory and antiplatelet effects. It is commonly used for its cardiovascular benefits and is prescribed as secondary prophylaxis after a heart attack. Furthermore, low-dose, long-term ASA is used to reduce the risk of heart attack and stroke in individuals without prior cardiovascular disease. Acetylsalicylic acid acts as a non-selective inhibitor of cyclooxygenase (COX), which inhibits the synthesis of prostaglandins and prevents pro-inflammatory cytokines. Findings suggest that targeting cytokines and growth factors could be a potential therapeutic strategy for reducing neuroinflammation and slowing down the progression of dementia. Additionally, prostaglandins contribute to synaptic plasticity and can act as retrograde messengers in synapses. Research has implicated COX-1, one of the isoforms of the enzyme, in neuroinflammation and neurodegenerative disorders. The inhibition of COX-1 might potentially prevent impairments in working memory and reduce neuroinflammation caused by beta-amyloid proteins in some conditions, such as Alzheimer's disease (AD). Cyclooxygenase-2, an inducible form of the enzyme, is expressed in cortical and hippocampal neurons and is associated with long-term synaptic plasticity. The inhibition or knockout of COX-2 has been shown to decrease long-term potentiation, a process involved in memory formation. Studies have also demonstrated that the administration of COX-2 inhibitors impairs cognitive function and memory acquisition and recall in animal models. There remains a debate regarding the effects of aspirin on dementia and cognitive decline. Although some studies suggest a possible protective effect of non-steroidal anti-inflammatory drugs, including aspirin, against the development of AD, others have shown inconsistent evidence. This review provides an overview of the effects of ASA or its active metabolite salicylate on learning, memory, and synaptic plasticity.

Antiplatelet Therapy in Patients With Abdominal Aortic Aneurysm Without Symptomatic Atherosclerotic Disease

Patients with abdominal aortic aneurysm have a high risk of ischemic events associated with concomitant atherosclerotic cardiovascular disease, and current clinical practice guidelines recommend antiplatelet therapy to mitigate this risk. However, in patients with aneurysms without symptomatic atherosclerosis, the benefit of antiplatelet therapy has been sparsely investigated. To estimate the effect of antiplatelets on the risk of ischemic events and bleeding in individuals with abdominal aneurysms with no symptomatic atherosclerotic vascular disease. A comparative effectiveness research study using a target trial emulation framework was performed. Population-based, cross-linked observational data from Danish national health registries containing comprehensive, individual-level information on all Danish citizens were used to evaluate patients who were antiplatelet-naive and diagnosed with abdominal aortic aneurysms, with no record of symptomatic atherosclerotic vascular disease, from January 1, 2010, through August 21, 2021. Prescription filled for aspirin or clopidogrel. Risk of ischemic events (myocardial infarction and/or ischemic stroke) and risk of major bleeding. For target trial emulation, trials were emulated as sequential, contingent on patient eligibility at the time of inclusion, and were evaluated by means of pooled logistic regression models to estimate the intention-to-treat and as-treated effects, expressed as hazard ratio (HR) and event-free survival. A total of 6344 patients (65.2% men; age, 72 [IQR, 64-78] years) provided 131 047 trial cases; 3363 of these cases involved initiation of antiplatelet therapy and 127 684 did not. A total of 182 ischemic events occurred among initiators and 5602 ischemic events occurred among noninitiators, corresponding to an intention-to-treat HR of 0.91 (95% CI, 0.73-1.17) and an estimated absolute event-free survival difference of -0.6% (95% CI, -1.7% to 0.5%). After censoring nonadherent person-time, the treatment HR was 0.90 (95% CI, 0.68-1.20), with similar risk difference. For bleeding, the intention-to-treat HR was 1.26 (95% CI, 0.97-1.58) and the event-free survival difference was 1.0%. The treatment HR was 1.21 (95% CI, 0.82-1.72); the risk difference was similar. In this study, no evidence of effectiveness of antiplatelet therapy to lower the risk of ischemic events and a trend toward higher bleeding risk was noted. The observed differences between the treatment groups were minimal, suggesting limited clinical relevance of antiplatelet treatment.

Platelet hyperactivity: a comparison of water-soluble, bioactive compound levels in commercial tomato products and water-soluble tomato concentrate, a supplement with an approved EFSA antiplatelet health effect

The aim of this study was to evaluate and compare the concentration of water-soluble bioactive compounds in tomato products (polyphenols profile, water-soluble vitamins and nucleophilic substances) with the concentration of the same bioactive molecules existing in a water-soluble patented tomato extract, water-soluble tomato extract (WSTC), commercially available as FruitFlow®. This patented tomato extract has been recognised by EFSA (European Food Safety Authority) in a specific Health Claim declaration as having an “Antiplatelet health effect”. More than 100 commercial tomato samples, coming from 18 different processing tomato companies worldwide, were analysed and compared with the FruitFlow® supplement. According to the multivariate statistical analyses applied to the data matrix, it is possible to conclude that the commercial tomato products measured (pastes, purees, others) show a significantly higher concentration of water-soluble bioactive molecules (nucleosides/nucleotides and polyphenols) responsible for an anti-platelet aggregation effect than the FruitFlow® dietary supplement.

Population pharmacokinetic-pharmacodynamic modeling of clopidogrel for dose regimen optimization based on CYP2C19 phenotypes: A proof of concept study.

Clopidogrel is an antiplatelet drug used to reduce the risk of acute coronary syndrome and stroke. It is converted by CYP2C19 to its active metabolite; therefore, poor metabolizers (PMs) of CYP2C19 exhibit diminished antiplatelet effects. Herein, we conducted a proof-of-concept study for using population pharmacokinetic-pharmacodynamic (PK-PD) modeling to recommend a personalized clopidogrel dosing regimen for individuals with varying CYP2C19 phenotypes and baseline P2Y12 reaction unit (PRU) levels. Data from a prospective phase I clinical trial involving 36 healthy male participants were used to develop the population PK-PD model predicting the concentrations of clopidogrel, clopidogrel H4, and clopidogrel carboxylic acid, and linking clopidogrel H4 concentrations to changes in PRU levels. A two-compartment model effectively described the PKs of both clopidogrel and clopidogrel carboxylic acid, and a one-compartment model of those of clopidogrel H4. The CYP2C19 phenotype was identified as a significant covariate influencing the metabolic conversion of the parent drug to its metabolites. A PD submodel of clopidogrel H4 that stimulated the fractional turnover rate of PRU levels showed the best performance. Monte Carlo simulations suggested that PMs require three to four times higher doses than extensive metabolizers to reach the target PRU level. Individuals within the top 20th percentile of baseline PRU levels were shown to require 2.5-3 times higher doses than those in the bottom 20th percentile. We successfully developed a population PK-PD model for clopidogrel considering the impact of CYP2C19 phenotypes and baseline PRU levels. Further studies are necessary to confirm actual dosing recommendations for clopidogrel.

Polysaccharide-rich extract of Genipa americana leaves exerts anti-inflammatory effects modulated by platelet mediators

Ethnopharmacological relevanceGenipa americana L. (Rubiaceae) leaves are traditionally used to treat fever, pharyngitis, healing, luxation and bruises. Aim of the studyThis study aimed to investigate the anti-inflammatory effect of the polysaccharide-rich extract of G. americana leaves (PE-Ga) in acute inflammation models and underlying mechanisms associated with platelet activity. Materials and methodsRats received PE-Ga (0.3–3.0 mg/kg; IV) 30 min before injection (IP or SC) of zymosan, serotonin, PGE2, PLA2, PAF or L-arginine, and evaluated in the models of paw edema and acute peritonits. The blockage of plasma serotonin reuptake into platelets was performed with fluoxetine (40 mg/kg; IP). ResultsIn vitro, PE-Ga inhibited ADP-induced platelet aggregation up to 49%. In the edema model, PE-Ga reduced (41%) the time-course of the edema induced by zymosan, mainly the last phase (62%), as well as that induced by PLA2 (32%), PAF (35%), L-arginine (36%), PGE2 (49%) or serotonin (54% AUC); and reversed paw hypernociception induced by PGE2 or serotonin. In the peritonitis model, PE-Ga reversed abdominal hypernociception and reduced leukocyte migration induced by zymosan to blood (38%) and peritoneal cavity (55%), mainly neutrophils (70%). PE-GA also decreased leukocyte rolling (32%) and adhesion (47%), and increased the rolling velocity 2.2-fold. In the peritoneal fluid, PE-Ga reversed P-selectin and reduced total proteins (17%), MDA (40%), NO2−/NO3− (27%), and MPO activity (43%) but increased catalase activity 3.3-fold compared to zymosan. In addition, fluoxetine reversed PE-Ga anti-inflammatory effect on leukocyte migration and adhesion. ConclusionsPE-Ga exerts antiplatelet and anti-inflammatory effects in acute inflammation induced by zymosan, being modulated by P-selectin and platelet serotonin, among other inflammatory mediators.