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Molecules (Basel, Switzerland) Dec 2022Acetylsalicylic acid (ASA) is one of the first drugs to be obtained by synthesis while being the most used. It has experienced the longest lasting commercial success and... (Review)
Review
Acetylsalicylic acid (ASA) is one of the first drugs to be obtained by synthesis while being the most used. It has experienced the longest lasting commercial success and is considered the most popular drug of the modern era. ASA, originally used as an anti-inflammatory medication, nowadays is predominantly used as an antiplatelet agent for prophylaxis in cardiac patients. Many studies show that the benefits of using ASA far outweigh the potential risk of side effects. With particular emphasis on the possibility of ASA repositioning for new therapies, extending the indications for use beyond the diseases from the spectrum of atherosclerotic diseases, such as cancer, requires shifting the benefit-risk ratio, although very good, even more towards safety. Interesting activities consisting not only of changing the formulation but also modifying the drug molecule seem to be an important goal of the 21st century. ASA has become a milestone in two important fields: pharmacy and medicine. For a pharmacist, ASA is a long-used drug for which individual indications are practically maintained. For a doctor, acetylsalicylic acid is primarily an antiplatelet drug that saves millions of lives of patients with coronary heart disease or after a stroke. These facts do not exempt us from improving therapeutic methods based on ASA, the main goal of which is to reduce the risk of side effects, as well as to extend effectiveness. Modified acetylsalicylic acid molecules already seem to be a promising therapeutic option.
Topics: Humans; Aspirin; Platelet Aggregation Inhibitors; Stroke
PubMed: 36500502
DOI: 10.3390/molecules27238412 -
British Journal of Anaesthesia Dec 2013Worldwide, cardiovascular events represent the major cause of morbidity and mortality. A key role in the pathogenesis of these events is played by platelets.... (Review)
Review
Worldwide, cardiovascular events represent the major cause of morbidity and mortality. A key role in the pathogenesis of these events is played by platelets. Interventional procedures, with placement of coronary and vascular stents, often represent the preferred therapeutic strategy. Antiplatelet medications are considered first-line therapy in preventing cardiovascular thrombotic events. A wide array of antiplatelet agents is available, each with different pharmacological properties. When patients on antiplatelet agents present for surgery, the perioperative team must design an optimal strategy to manage antiplatelet medications. Each patient is stratified according to risk of developing a cardiovascular thrombotic event and inherent risk of surgical bleeding. After risk stratification analysis, various therapeutic pathways include continuing or discontinuing all antiplatelet agents or maintaining one antiplatelet agent and discontinuing the other. This review focuses on the pharmacological and pharmacokinetic properties of both older and novel antiplatelet drugs, and reviews current literature and guidelines addressing options for perioperative antiplatelet management.
Topics: Aspirin; Blood Coagulation; Coronary Artery Disease; Humans; Perioperative Care; Platelet Activation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Stroke
PubMed: 24335397
DOI: 10.1093/bja/aet402 -
Journal of Thrombosis and Haemostasis :... Jul 2009Although conceived at the end of the 19th century as a synthetic analgesic agent with improved gastric tolerability vs. naturally occurring salicylates, acetylsalicylic... (Review)
Review
Although conceived at the end of the 19th century as a synthetic analgesic agent with improved gastric tolerability vs. naturally occurring salicylates, acetylsalicylic acid (marketed as aspirin in 1899) turned out to be an ideal antiplatelet agent about 90 years later, following the understanding of its mechanism of action, the development of a mechanism-based biomarker for dose-finding studies, and the initiation of a series of appropriately sized, randomized clinical trials to test its efficacy and safety at low doses given once daily. At the turn of its 110th anniversary, aspirin continues to attract heated debates on a number of issues including (i) the optimal dose to maximize efficacy and minimize toxicity; (ii) the possibility that some patients may be 'resistant' to its antiplatelet effects; and (iii) the balance of benefits and risks in primary vs. secondary prevention.
Topics: Aspirin; Drug Resistance; History, 20th Century; History, 21st Century; Humans; Platelet Aggregation Inhibitors; Risk Assessment
PubMed: 19630812
DOI: 10.1111/j.1538-7836.2009.03391.x -
Scientific Reports Dec 2020Neointima hyperplasia is a crucial component of restenosis after coronary angioplasty. We have hypothesized that enhanced generation of platelet-derived thromboxane...
Neointima hyperplasia is a crucial component of restenosis after coronary angioplasty. We have hypothesized that enhanced generation of platelet-derived thromboxane (TX)A in response to vascular damage plays a critical role in neointimal hyperplasia and that antiplatelet agents may mitigate it. In cocultures of human platelets and coronary artery smooth muscle cells (CASMC), we found that platelets induced morphologic changes and enhanced the migration of CASMC. The exposure of platelets to Aspirin [an inhibitor of cyclooxygenase (COX)-1] reduced the generation of TXA and prevented the morphological and functional changes induced by platelets in CASMC. Platelet-derived TXA induced COX-2 and enhanced prostaglandin (PG)E biosynthesis in CASMC, a known mechanism promoting neointimal hyperplasia. COX-2 induction was prevented by different antiplatelet agents, i.e., Aspirin, the TP antagonist SQ29,548, or Revacept (a dimeric soluble GPVI-Fc fusion protein). The administration of the novel antiplatelet agent Revacept to C57BL/6 mice, beginning three days before femoral artery denudation, and continuing up to seven days after injury, prevented the increase of the systemic biosynthesis di TXA and reduced femoral artery intima-to-media area and the levels of markers of cell proliferation and macrophage infiltration. Revacept might serve as a therapeutic agent for percutaneous coronary angioplasty and stent implantation.
Topics: Adult; Animals; Blood Platelets; Cell Movement; Cell Proliferation; Coculture Techniques; Coronary Vessels; Cyclooxygenase 2; Glycoproteins; Humans; Hyperplasia; Immunoglobulin Fc Fragments; Male; Mice; Myocytes, Smooth Muscle; Neointima; Platelet Aggregation Inhibitors; Thromboxane A2; Urine; Young Adult
PubMed: 33293599
DOI: 10.1038/s41598-020-77934-x -
The Cochrane Database of Systematic... Feb 2022Antiplatelet agents are widely used to prevent cardiovascular events. The risks and benefits of antiplatelet agents may be different in people with chronic kidney... (Review)
Review
BACKGROUND
Antiplatelet agents are widely used to prevent cardiovascular events. The risks and benefits of antiplatelet agents may be different in people with chronic kidney disease (CKD) for whom occlusive atherosclerotic events are less prevalent, and bleeding hazards might be increased. This is an update of a review first published in 2013.
OBJECTIVES
To evaluate the benefits and harms of antiplatelet agents in people with any form of CKD, including those with CKD not receiving renal replacement therapy, patients receiving any form of dialysis, and kidney transplant recipients.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 13 July 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
We selected randomised controlled trials of any antiplatelet agents versus placebo or no treatment, or direct head-to-head antiplatelet agent studies in people with CKD. Studies were included if they enrolled participants with CKD, or included people in broader at-risk populations in which data for subgroups with CKD could be disaggregated.
DATA COLLECTION AND ANALYSIS
Four authors independently extracted data from primary study reports and any available supplementary information for study population, interventions, outcomes, and risks of bias. Risk ratios (RR) and 95% confidence intervals (CI) were calculated from numbers of events and numbers of participants at risk which were extracted from each included study. The reported RRs were extracted where crude event rates were not provided. Data were pooled using the random-effects model. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
MAIN RESULTS
We included 113 studies, enrolling 51,959 participants; 90 studies (40,597 CKD participants) compared an antiplatelet agent with placebo or no treatment, and 29 studies (11,805 CKD participants) directly compared one antiplatelet agent with another. Fifty-six new studies were added to this 2021 update. Seven studies originally excluded from the 2013 review were included, although they had a follow-up lower than two months. Random sequence generation and allocation concealment were at low risk of bias in 16 and 22 studies, respectively. Sixty-four studies reported low-risk methods for blinding of participants and investigators; outcome assessment was blinded in 41 studies. Forty-one studies were at low risk of attrition bias, 50 studies were at low risk of selective reporting bias, and 57 studies were at low risk of other potential sources of bias. Compared to placebo or no treatment, antiplatelet agents probably reduces myocardial infarction (18 studies, 15,289 participants: RR 0.88, 95% CI 0.79 to 0.99, I² = 0%; moderate certainty). Antiplatelet agents has uncertain effects on fatal or nonfatal stroke (12 studies, 10.382 participants: RR 1.01, 95% CI 0.64 to 1.59, I² = 37%; very low certainty) and may have little or no effect on death from any cause (35 studies, 18,241 participants: RR 0.94, 95 % CI 0.84 to 1.06, I² = 14%; low certainty). Antiplatelet therapy probably increases major bleeding in people with CKD and those treated with haemodialysis (HD) (29 studies, 16,194 participants: RR 1.35, 95% CI 1.10 to 1.65, I² = 12%; moderate certainty). In addition, antiplatelet therapy may increase minor bleeding in people with CKD and those treated with HD (21 studies, 13,218 participants: RR 1.55, 95% CI 1.27 to 1.90, I² = 58%; low certainty). Antiplatelet treatment may reduce early dialysis vascular access thrombosis (8 studies, 1525 participants) RR 0.52, 95% CI 0.38 to 0.70; low certainty). Antiplatelet agents may reduce doubling of serum creatinine in CKD (3 studies, 217 participants: RR 0.39, 95% CI 0.17 to 0.86, I² = 8%; low certainty). The treatment effects of antiplatelet agents on stroke, cardiovascular death, kidney failure, kidney transplant graft loss, transplant rejection, creatinine clearance, proteinuria, dialysis access failure, loss of primary unassisted patency, failure to attain suitability for dialysis, need of intervention and cardiovascular hospitalisation were uncertain. Limited data were available for direct head-to-head comparisons of antiplatelet drugs, including prasugrel, ticagrelor, different doses of clopidogrel, abciximab, defibrotide, sarpogrelate and beraprost.
AUTHORS' CONCLUSIONS
Antiplatelet agents probably reduced myocardial infarction and increased major bleeding, but do not appear to reduce all-cause and cardiovascular death among people with CKD and those treated with dialysis. The treatment effects of antiplatelet agents compared with each other are uncertain.
Topics: Humans; Platelet Aggregation Inhibitors; Proteinuria; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 35224730
DOI: 10.1002/14651858.CD008834.pub4 -
Thrombosis Research Jun 2024Hypolipidemia and platelet activation play key roles in atherosclerotic diseases. Pirinixic acid (WY-14643) was originally developed as a lipid-lowering drug. Here we...
BACKGROUND AND PURPOSE
Hypolipidemia and platelet activation play key roles in atherosclerotic diseases. Pirinixic acid (WY-14643) was originally developed as a lipid-lowering drug. Here we focused on its antiplatelet and antithrombotic abilities and the underlying mechanism.
EXPERIMENTAL APPROACH
The effects of WY-14643 on platelet aggregation was measured using a lumi-aggregometer. Clot retraction and spreading on fibrinogen were also assayed. PPARα platelets were used to identify the target of WY-14643. The interaction between WY-14643 and glycoprotein Ibα (GPIbα) was detected using cellular thermal shift assay (CETSA), surface plasmon resonance (SPR) spectroscopy and molecular docking. GPIbα downstream signaling was examined by Western blot. The antithrombotic effect was investigated using mouse mesenteric arteriole thrombosis model. Mouse tail bleeding model was used to study its effect on bleeding side effects.
KEY RESULTS
WY-14643 concentration-dependently inhibits human washed platelet aggregation, clot retraction, and spreading. Significantly, WY-14643 inhibits thrombin-induced activation of human washed platelets with an IC of 7.026 μM. The antiplatelet effect of WY-14643 is mainly dependent of GPIbα. CESTA, SPR and molecular docking results indicate that WY-14643 directly interacts with GPIbα and acts as a GPIbα antagonist. WY-14643 also inhibits phosphorylation of PLCγ2, Akt, p38, and Erk1/2 induced by thrombin. Noteworthily, 20 mg/kg oral administration of WY-14643 inhibits FeCl-induced thrombosis of mesenteric arteries in mice similarly to clopidogrel without increasing bleeding.
CONCLUSION AND IMPLICATIONS
WY-14643 is not only a PPARα agonist with lipid-lowering effect, but also an antiplatelet agent as a GPIbα antagonist. It may have more significant therapeutic advantages than current antiplatelet agents for the treatment of atherosclerotic thrombosis, which have lipid-lowering effects without bleeding side effects.
Topics: Animals; Mice; Platelet Glycoprotein GPIb-IX Complex; Humans; Fibrinolytic Agents; Platelet Aggregation Inhibitors; Pyrimidines; Platelet Aggregation; Thrombosis; Blood Platelets; Male; Molecular Docking Simulation; Mice, Inbred C57BL
PubMed: 38669962
DOI: 10.1016/j.thromres.2024.04.011 -
Turk Kardiyoloji Dernegi Arsivi : Turk... Mar 2018In cardiology practice, anticoagulation and antiplatelet therapies are essential for most patients. As of yet, there is no high quality evidence regarding these... (Review)
Review
In cardiology practice, anticoagulation and antiplatelet therapies are essential for most patients. As of yet, there is no high quality evidence regarding these treatments in thrombocytopenic patients, which continues to be an issue. Thrombocytopenia is defined as a platelet count of <150x109/L and is classified as severe when the platelet count is <50x109/L. Pseudothrombocytopenia, drug-induced thrombocytopenia, immune thrombocytopenia, heparin-induced thrombocytopenia, and thrombotic thrombocytopenic purpura are some of the main causes of thrombocytopenia. The current treatment suggestions are conservative, as a result of the lack of evidence, built on defensive treatment strategies and the fear of bleeding complications. Many patients with acute myocardial infarction with thrombocytopenia have undergone percutaneous coronary intervention successfully with adjunctive antiplatelet and anticoagulant use, as has been described in case reports. A risk-benefit ratio should be evaluated for antiplatelet therapy. In the relevant guidelines, while full dose low-molecular-weight heparin (LMWH) is recommended for patients with a thrombocyte count of >50x109/L, a half-dose of LMWH is recommended in patients with thrombocytopenia between 25 and 50x109/L. According to the current guidelines, avoiding antiplatelet and anticoagulant treatment should be restricted to patients with very severe thrombocytopenia (i.e., a platelet count <25x109/L), but new data and recommendations are needed.
Topics: Anticoagulants; Cardiovascular Surgical Procedures; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Thrombocytopenia
PubMed: 29512619
DOI: 10.5543/tkda.2018.76968 -
Molecules (Basel, Switzerland) Jun 2016Adverse effects and drug resistance to the current onchopharmacologicals have increased the demand for alternative novel therapeutics. We herein introduce justicidin B,... (Review)
Review
Adverse effects and drug resistance to the current onchopharmacologicals have increased the demand for alternative novel therapeutics. We herein introduce justicidin B, an arylnaphthalen lignan isolated from different plant origins, especially Justicia, Phyllanthus, Haplophyllum and Linum species. This cyclolignan exhibits a wide array of biological properties ranges from piscicidal to antifungal, antiviral and antibacterial activities. Activity against Trypanosoma brucei makes justicidin B a potential antiprotozoal agent for the treatment of neglected tropical diseases. Pharmacological properties like antiplatelet, anti-inflammatory and bone resorption inhibition have been also attributed to justicidin B. This compound is a potent cytotoxic substance on several cell lines, especially chronic myeloid and chronic lymphoid leukemia. Pharmacological values, natural variation, as well as biotechnological production of justicidin B by plant cell, tissue and organ culture are also described in this review. Chemical characteristics and chromatographic methods to identify justicidin B and its biosynthetic pathway have been discussed. Different approaches to the total synthesis of justicidin B are compared. This review would shed light on the role of justicidin B as an intriguing natural compound and provides a chance to optimize conditions for industrial applications.
Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antiprotozoal Agents; Biological Products; Biosynthetic Pathways; Biotechnology; Chemistry; Dioxolanes; Humans; Lignans; Metabolomics; Plant Extracts; Platelet Aggregation Inhibitors; Toxicity Tests
PubMed: 27347906
DOI: 10.3390/molecules21070820 -
Journal of Vascular Surgery Nov 2014Bypass surgery is regularly performed for the treatment of critical limb ischemia, but the risk of occlusion remains significant. Antiplatelet therapy in patients with... (Review)
Review
OBJECTIVE
Bypass surgery is regularly performed for the treatment of critical limb ischemia, but the risk of occlusion remains significant. Antiplatelet therapy in patients with arterial disease is useful for secondary cardiovascular and bypass occlusion prevention. However, despite the common use of an antiplatelet agent, especially aspirin, which became the standard of care, the risk of graft occlusion persists. The best antithrombotic treatment for bypass patency therefore remains a matter of debate.
METHODS
We conducted a systematic literature search to identify studies and consensus reporting the use of antithrombotic treatment to prevent bypass occlusion. We excluded case reports and clinical trials with a placebo arm.
RESULTS
Aspirin remains the mainstay of treatment to improve infrainguinal bypass patency; however, the effect differs according to the bypass material used. The greatest beneficial effect of antiplatelet agents was observed with prosthetic bypasses. In such cases, the addition of clopidogrel to aspirin, for at least 1 year, in patients who benefited from a below-knee bypass graft significantly improved bypass patency (occlusion 32% vs 47% for aspirin alone; P = .02) and the amputation rate (9.4% vs 19.2% for aspirin alone; P = .03), without increasing the incidence of major hemorrhage. In contrast, antiplatelet regimens were less efficacious for autologous vein bypasses. The addition of a vitamin K antagonist (VKA) is not routinely proposed because of the increased incidence of associated major hemorrhage. The use of VKA alone, instead of aspirin, should probably be discussed in selected patients, and a combination of VKA and antiplatelet agents should be discussed in patients with venous infrainguinal bypasses considered to be at a high risk for occlusion.
CONCLUSIONS
Although aspirin remains the first-line treatment to prevent infrainguinal bypass occlusion, future studies are needed to define stronger recommendations.
Topics: Administration, Oral; Blood Vessel Prosthesis Implantation; Critical Illness; Fibrinolytic Agents; Graft Occlusion, Vascular; Humans; Ischemia; Odds Ratio; Platelet Aggregation Inhibitors; Postoperative Hemorrhage; Risk Factors; Treatment Outcome; Vascular Patency; Veins
PubMed: 25441694
DOI: 10.1016/j.jvs.2014.07.105 -
International Journal of Molecular... Dec 2021Over the last decades, antiplatelet agents, mainly aspirin and P2Y receptor antagonists, have significantly reduced morbidity and mortality associated with arterial... (Review)
Review
Over the last decades, antiplatelet agents, mainly aspirin and P2Y receptor antagonists, have significantly reduced morbidity and mortality associated with arterial thrombosis. Their pharmacological characteristics, including pharmacokinetic/pharmacodynamics profiles, have been extensively studied, and a significant number of clinical trials assessing their efficacy and safety in various clinical settings have established antithrombotic efficacy. Notwithstanding, antiplatelet agents carry an inherent risk of bleeding. Given that bleeding is associated with adverse cardiovascular outcomes and mortality, there is an unmet clinical need to develop novel antiplatelet therapies that inhibit thrombosis while maintaining hemostasis. In this review, we present the currently available antiplatelet agents, with a particular focus on their targets, pharmacological characteristics, and patterns of use. We will further discuss the novel antiplatelet therapies in the pipeline, with the goal of improved clinical outcomes among patients with atherothrombotic diseases.
Topics: Cardiovascular Diseases; Humans; Platelet Aggregation Inhibitors
PubMed: 34884884
DOI: 10.3390/ijms222313079