Antiplatelet drugs reduce the risks associated with atherothrombotic events and show various applications in diverse cardiovascular diseases including myocardial infarctions. Efficacy of the current antiplatelet medicines including aspirin, clopidogrel, prasugrel and ticagrelor, and the glycoprotein IIb/IIIa antagonists, are limited due to their increased risks of bleeding, and antiplatelet drug resistance. Hence, it is important to develop new effective antiplatelet drugs, with fewer side-effects. The vast repertoire of natural peptides can be explored towards this goal. Proteins and peptides derived from snake venoms and plants represent exciting candidates for the development of novel and potent antiplatelet agents. Consequently, this review discusses multiple peptides that have displayed antiplatelet aggregation activity in preclinical drug development stages. This review also describes the antiplatelet mechanisms of the peptides, emphasizing the signaling pathways intervened by them. Also, the hurdles encountered during the development of peptides into antiplatelet drugs have been listed. Finally, hitherto unexplored peptides with the potential to prevent platelet aggregation are explored.

• Klíčová slova
• antiplatelet effects, bioactive peptides, cardiovascular disease, drug discovery, medicinal plants, pharmacokinetic profile,
• MeSH
• dietní proteiny terapeutické užití   MeSH
• inhibitory agregace trombocytů terapeutické užití   MeSH
• lidé MeSH
• peptidy farmakokinetika   terapeutické užití   MeSH
• preklinické hodnocení léčiv MeSH
• proteiny terapeutické užití   MeSH
• rostliny chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• dietní proteiny MeSH
• inhibitory agregace trombocytů MeSH
• peptidy MeSH
• proteiny MeSH

BACKGROUND: Antiplatelet drugs represent the keystone in the treatment and prevention of diseases of ischemic origin, including coronary artery disease. The current palette of drugs represents efficient modalities in most cases, but their effect can be limited in certain situations or associated with specific side effects. In this study, representatives of compounds selected from series having scaffolds with known or potential antiplatelet activity were tested. These compounds were previously synthetized by us, but their biological effects have not yet been reported. OBJECTIVE: The aim of this study was to examine the antiplatelet and anticoagulation properties of selected compounds and determine their mechanism of action. METHODS: Antiplatelet activity of compounds and their mechanisms of action were evaluated using human blood by impedance aggregometry and various aggregation inducers and inhibitors and compared to appropriate standards. Cytotoxicity was tested using breast adenocarcinoma cell cultures and potential anticoagulation activity was also determined. RESULTS: In total, four of 34 compounds tested were equally or more active than the standard antiplatelet drug Acetylsalicylic Acid (ASA). In contrast to ASA, all 4 active compounds decreased platelet aggregation triggered not only by collagen, but also partly by ADP. The major mechanism of action is based on antagonism at thromboxane receptors. In higher concentrations, inhibition of thromboxane synthase was also noted. In contrast to ASA, the tested compounds did not block cyclooxygenase- 1. CONCLUSION: The most active compound, 2-amino-4-(1H-indol-3-yl)-6-nitro-4H-chromene-3- carbonitrile (2-N), which is 4-5x times more potent than ASA, is a promising compound for the development of novel antiplatelet drugs.

• Klíčová slova
• Pyridopyrimidine, acridine, aggregation, coagulation, coumarin, indole,
• MeSH
• agregace trombocytů MeSH
• Aspirin farmakologie   MeSH
• heterocyklické sloučeniny * farmakologie   MeSH
• inhibitory agregace trombocytů * farmakologie   MeSH
• lidé MeSH
• trombocyty MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Aspirin MeSH
• heterocyklické sloučeniny * MeSH
• inhibitory agregace trombocytů * MeSH

OBJECTIVES: Both pyridine and pyrano derivatives have been previously shown to possess biologically relevant activity. In this study, we report the incorporation of these two scaffolds into one molecule. METHODS: The designed 3,3-dimethyl-6-oxopyrano[3,4-c]pyridines were synthesized by the acylation of enamine under Stork conditions followed by condensation of formed β-diketones with 2-cyanoacetamide. The structures of these compounds were confirmed by using a wide spectrum of physico-chemical methods. Their antiplatelet, anticoagulant and vasodilatory activity together with toxicity were evaluated. KEY FINDINGS: A series of 6-oxopyrano[3,4-c]pyridines 3a-j was obtained. Four of these compounds were reported for the first time. None of the tested compounds demonstrated anticoagulant effect but 8-methyl derivative (3a) was a potent antiplatelet compound with IC50 numerically twice as low as the clinically used acetylsalicylic acid. A series of further mechanistic tests showed that 3a interferes with calcium signaling. The compound is also not toxic and in addition possesses vasodilatory activity as well. CONCLUSIONS: Compound 3a is a promising inhibitor of platelet aggregation, whose mechanism of action should be studied in detail.

• Klíčová slova
• anticoagulant, antiplatelet activity, cytotoxicity, pyranopyridine, vasodilatory, β-diketones,
• MeSH
• agregace trombocytů * MeSH
• antikoagulancia farmakologie   MeSH
• inhibitory agregace trombocytů * chemie   farmakologie   MeSH
• pyridiny farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikoagulancia MeSH
• inhibitory agregace trombocytů * MeSH
• pyridiny MeSH

BACKGROUND: Nonadherence to antiplatelet therapy after percutaneous coronary intervention (PCI) is common, even in clinical trials. OBJECTIVES: The purpose of this study was to investigate the impact of nonadherence to study protocol regimens in the MASTER DAPT (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Prolonged DAPT Regimen) trial. METHODS: At 1-month after PCI, 4,579 high bleeding risk patients were randomized to single antiplatelet therapy (SAPT) for 11 months (or 5 months in patients on oral anticoagulation [OAC]) or dual antiplatelet therapy (DAPT) for ≥2 months followed by SAPT. Coprimary outcomes included net adverse clinical events (NACE), major adverse cardiac and cerebral events (MACE), and major or clinically relevant nonmajor bleeding (MCB) at 335 days. Inverse probability-of-censoring weights were used to correct for nonadherence Academic Research Consortium type 2 or 3. RESULTS: In total, 464 (20.2%) patients in the abbreviated-treatment and 214 (9.4%) in the standard-treatment groups incurred nonadherence Academic Research Consortium type 2 or 3. At inverse probability-of-censoring weights analyses, NACE (HR: 1.01; 95% CI: 0.88-1.27) or MACE (HR: 1.07; 95% CI: 0.83-1.40) did not differ, and MCB was lower with abbreviated compared with standard treatment (HR: 0.51; 95% CI: 0.60-0.73) consistently across OAC subgroups; among OAC patients, SAPT discontinuation 6 months after PCI was associated with similar MACE and lower MCB (HR: 0.47; 95% CI: 0.22-0.99) compared with SAPT continuation. CONCLUSIONS: In the MASTER DAPT adherent population, 1-month compared with ≥3-month DAPT was associated with similar NACE or MACE and lower MCB. Among OAC patients, SAPT discontinuation after 6 months was associated with similar MACE and lower MCB than SAPT continuation (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Prolonged DAPT Regimen [MASTER DAPT]; NCT03023020).

• Klíčová slova
• P2Y(12) inhibitor, acetylsalicylic acid, drug-eluting stent, dual antiplatelet therapy, high bleeding risk,
• MeSH
• adherence k farmakoterapii MeSH
• inhibitory agregace trombocytů terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• koronární angioplastika * metody   MeSH
• krvácení chemicky indukované   farmakoterapie   epidemiologie   MeSH
• lidé MeSH
• polymery MeSH
• stenty uvolňující léky * škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• inhibitory agregace trombocytů MeSH
• polymery MeSH

To date, there are no sufficient data to make firm recommendations on the treatment of patients with severe thrombocytopenia who require antiplatelet therapy after experiencing acute coronary syndrome. Therefore, we think that it is important to communicate the experience with individual cases. We report the case of a patient who presented with pericardial effusion causing cardiac tamponade. He had thrombocytopenia associated with myelodysplastic syndrome, and ten weeks before this admission, percutaneous transluminal coronary angioplasty with implantation of drug-eluting stents was performed for non-ST-segment elevation acute coronary syndrome. Platelets in myelodysplastic syndromes are dysfunctional, which exacerbates bleeding from thrombocytopenia, and the management of atherosclerotic cardiovascular disease in these patients is challenging.

• Klíčová slova
• acute coronary syndrome, antiplatelet therapy, clopidogrel, drug-eluting stents, myelodysplastic syndromes, thrombocytopenia,
• MeSH
• akutní koronární syndrom terapie   MeSH
• inhibitory agregace trombocytů škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• myelodysplastické syndromy komplikace   MeSH
• nemoci koronárních tepen terapie   MeSH
• perikardiální efuze komplikace   MeSH
• senioři MeSH
• srdeční tamponáda etiologie   MeSH
• stenty uvolňující léky MeSH
• trombocytopenie komplikace   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• inhibitory agregace trombocytů MeSH

Flavonoids are associated with positive cardiovascular effects. However, due to their low bioavailability, metabolites are likely responsible for these properties. Recently, one of these metabolites, 4-methylcatechol, was described to be a very potent antiplatelet compound. This study aimed to compare its activity with its 22 close derivatives both of natural or synthetic origin in order to elucidate a potential structure-antiplatelet activity relationship. Blood from human volunteers was induced to aggregate by arachidonic acid (AA), collagen or thrombin, and plasma coagulation was also studied. Potential toxicity was tested on human erythrocytes as well as on a cancer cell line. Our results indicated that 17 out of the 22 compounds were very active at a concentration of 40 μM and, importantly, seven of them had an IC50 on AA-triggered aggregation below 3 μM. The effects of the most active compounds were confirmed on collagen-triggered aggregation too. None of the tested compounds was toxic toward erythrocytes at 50 μM and four compounds partly inhibited proliferation of breast cancer cell line at 100 μM but not at 10 μM. Additionally, none of the compounds had a significant effect on blood coagulation or thrombin-triggered aggregation. This study hence reports four phenol derivatives (4-ethylcatechol, 4-fluorocatechol, 2-methoxy-4-ethylphenol and 3-methylcatechol) suitable for future in vivo testing.

• Klíčová slova
• 4-methylcatechol, aggregation, catechol, flavonoid, platelet, whole blood,
• MeSH
• agregace trombocytů * MeSH
• fenol * MeSH
• fenoly farmakologie   MeSH
• inhibitory agregace trombocytů farmakologie   MeSH
• lidé MeSH
• thrombin farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fenol * MeSH
• fenoly MeSH
• inhibitory agregace trombocytů MeSH
• thrombin MeSH

BACKGROUND: One reason for the lower incidence of cardiovascular diseases in Asian countries may be the high intake of isoflavonoids and their antiplatelet effects may be an important factor. To date, there is limited comparison of a range of isoflavonoids and knowledge of their effects at different levels of platelet aggregation. PURPOSE: To screen the antiplatelet effects of a number of isoflavonoids on the arachidonic acid based aggregation pathway and investigate how the antiplatelet activity might occur. METHODS: The antiplatelet effects were first screened in whole human blood where platelet aggregation was induced by arachidonic acid. Further analysis was targeted at search of the mechanism of action. RESULTS: Thirteen of the eighteen tested isoflavonoids had significant inhibitory effect on platelet aggregation in whole human blood. Genistein had the same potency as clinically used acetylsalicylic acid (ASA) while tectorigenin was clearly stronger than ASA. Further analyses showed that the effect of tectorigenin was not based on inhibition of cyclooxygenase-1 in contrast to ASA or thromboxane synthase but by competitive antagonism at thromboxane receptors. CONCLUSION: Tectorigenin is a more potent antiplatelet compound than ASA and thus an interesting substance for further testing.

• Klíčová slova
• Cyclooxygenase, Isoflavones, Platelets, Tectorigenin,
• MeSH
• agregace trombocytů účinky léků   MeSH
• Aspirin farmakologie   MeSH
• cyklooxygenasa 1 metabolismus   MeSH
• genistein farmakologie   MeSH
• inhibitory agregace trombocytů farmakologie   MeSH
• isoflavony farmakologie   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Aspirin MeSH
• cyklooxygenasa 1 MeSH
• genistein MeSH
• inhibitory agregace trombocytů MeSH
• isoflavony MeSH
• PTGS1 protein, human MeSH Prohlížeč
• tectorigenin MeSH Prohlížeč

The current practice of withdrawing aspirin 7-10 days preoperatively may be dangerous in certain groups of patients. The risk of cardiovascular events increases 3-fold after aspirin withdrawal. The average time between aspirin withdrawal and the manifestation of acute coronary syndrome is 8 to 11 days. The withdrawal of clopidogrel earlier than 4-6 weeks after bare metal stent implantation or less than 12 months after drug-eluting stent implantation is very risky and poses a high risk of stent thrombosis and high perioperative mortality. Continuing aspirin perioperatively leads to a 1.5-fold increase in perioperative bleeding complications but it does not lead to a higher severity of bleeding complications or higher mortality. The article analyzes current European and American guidelines for perioperative antiplatelet treatment and suggests an algorithm based on the guidelines to help make clinical decisions.

• MeSH
• akutní koronární syndrom prevence a kontrola   MeSH
• Aspirin aplikace a dávkování   škodlivé účinky   MeSH
• časové faktory MeSH
• inhibitory agregace trombocytů aplikace a dávkování   škodlivé účinky   MeSH
• klopidogrel MeSH
• kombinovaná farmakoterapie MeSH
• krvácení chemicky indukované   prevence a kontrola   MeSH
• lidé MeSH
• medicína založená na důkazech MeSH
• perioperační období * MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• stenty MeSH
• tiklopidin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• trombóza etiologie   prevence a kontrola   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• Aspirin MeSH
• inhibitory agregace trombocytů MeSH
• klopidogrel MeSH
• tiklopidin MeSH

SCOPE: Intake of flavonoids from the diet can be substantial, and epidemiological studies suggest that these compounds can decrease the incidence of cardiovascular diseases by involvement with increased platelet aggregation. Although parent flavonoids possess antiplatelet effects, the clinical importance is disputable due to their very low bioavailability. Most of them are metabolized by human colon bacteria to smaller phenolic compounds, which reach higher plasma concentrations than the parent flavonoids. In this study, a series of 29 known flavonoid metabolites is tested for antiplatelet potential. METHODS AND RESULTS: Four compounds appear to have a biologically relevant antiplatelet effect using whole human blood. 4-Methylcatechol (4-MC) is clearly the most efficient being about 10× times more active than clinically used acetylsalicylic acid. This ex vivo effect is also confirmed using a potentially novel in-vivo-like ex ovo hen's egg model of thrombosis, where 4-MC significantly increases the survival of the eggs. The mechanism of action is studied and it seems that it is mainly based on the influence on intracellular calcium signaling. CONCLUSION: This study shows that some flavonoid metabolites formed by human microflora have a strong antiplatelet effect. This information can help to explain the antiplatelet potential of orally given flavonoids.

• Klíčová slova
• 4-methylcatechol, aggregation, flavonoids, metabolites, platelets, pyrogallol,
• MeSH
• agregace trombocytů účinky léků   MeSH
• inhibitory agregace trombocytů farmakologie   MeSH
• inhibitory cyklooxygenasy farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• katecholy farmakologie   MeSH
• kuřecí embryo MeSH
• kyselina arachidonová farmakologie   MeSH
• lidé MeSH
• preklinické hodnocení léčiv metody   MeSH
• pyrogalol farmakologie   MeSH
• serotonin metabolismus   MeSH
• thromboxan-A synthasa antagonisté a inhibitory   MeSH
• trombóza farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• kuřecí embryo MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 4-methylcatechol MeSH Prohlížeč
• inhibitory agregace trombocytů MeSH
• inhibitory cyklooxygenasy MeSH
• inhibitory enzymů MeSH
• katecholy MeSH
• kyselina arachidonová MeSH
• pyrogalol MeSH
• serotonin MeSH
• thromboxan-A synthasa MeSH

BACKGROUND: Carotid stenting requires dual antiplatelet therapy to effectively prevent thromboembolic complications. However, resistance to clopidogrel, a key component of this therapy, may lead to persistent risk of these complications. The aim of this study was to determine, if the implementation of routine platelet function testing and adjusting therapy was associated with lower incidence of thromboembolic complications and death. METHODS: All consecutive patients treated with carotid artery stenting in a single institution over 8 years were enlisted in a retrospective study. Platelet function testing was performed, and efficient antiplatelet therapy was set before the procedure. Incidence of procedure-related stroke or death within periprocedural period (0-30 days) was assessed. The results were evaluated in relation to the findings of six prominent randomized control trials. RESULTS: A total of 241 patients were treated for carotid stenosis, seven patients undergo CAS on both sides over time. There was 138 symptomatic (55,6%) and 110 asymptomatic stenoses (44,4%). Five thromboembolic complications (2,01%) occurred, four of them (1,61%) was procedure-related. Two patients died because of procedure-related stroke (0,82%). Incidence of procedure-related stroke or death was significant lower compared to the results of CREST study (2,01% vs. 4,81%, P = 0,0243) in the entire cohorts, and to the results of ICSS study in the symptomatic cohorts (2,86% vs. 7,37%, P = 0,0243), respectively. CONCLUSIONS: Tailored antiplatelet therapy in carotid stenting is safe and seems to be related with lower incidence of procedure-related death or stroke rate. Larger prospective studies to assess whether platelet function testing-guided antiplatelet therapy is superior to standard dual antiplatelet should be considered.

• Klíčová slova
• Antiplatelet therapy, Carotid stenosis, Carotid stenting,
• Publikační typ
• časopisecké články MeSH