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.
- 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
Kyselina acetylsalicylová je efektivním a všeobecně uznávaným základním lékem v sekundární prevenci ischemických příhod. Její role v primární prevenci je studována několik desetiletí a stále zůstává kontroverzní. Prvotní studie prokazovaly redukci infarktů myokardu i ischemických iktů, bez ovlivnění celkové nebo kardiovaskulární mortality, ale zařazené subjekty nebyly v rámci primárně preventivní péče léčeny moderními léky a postupy tak jako dnes. Nedávno publikované studie také neprokázaly mortalitní benefit, ale u některých sub‐populací a skupin pacientů klinický přínos aspirinu nadále převažuje nad riziky spojenými s jeho dlouhodobým užíváním. V tomto přehledovém článku bude probrán vývoj ASA v primární prevenci, výsledky nejnovějších studií roku 2018 a jejich meta‐analýz, současné indikace léčby ASA a také výhledy do budoucna.
Acetylsalicylic acid is an effective and widely accepted essential drug in the secondary prevention of ischemic events. Its role in primary prevention has been studied for several decades and still remains controversial. Initial studies showed a reduction in both myocardial infarctions and ischemic strokes, without affecting overall or cardiovascular mortality, but the enrolled subjects were not treated with modern drugs and procedures in primary preventive care as they do today. Recently published studies have also not shown a mortality benefit, but in some sub-populations and groups of patients, the clinical benefit of aspirin continues to outweigh the risks associated with its long-term use. This review article will discuss the development of ASA in primary prevention, the results of the latest studies of the year 2018 and their meta-analyses, current indications for ASA treatment, as well as future perspectives.
- MeSH
- Aspirin * farmakologie terapeutické užití MeSH
- kardiovaskulární nemoci * prevence a kontrola MeSH
- lidé MeSH
- primární prevence MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. METHODS: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). RESULTS: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively). CONCLUSIONS: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. IMPACT: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.
- MeSH
- Aspirin farmakologie terapeutické užití MeSH
- kolorektální nádory farmakoterapie MeSH
- lidé MeSH
- mendelovská randomizace metody MeSH
- proteomika metody MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
- MeSH
- Aspirin * dějiny farmakologie terapeutické užití MeSH
- cévní mozková příhoda mortalita prevence a kontrola MeSH
- infarkt myokardu mortalita prevence a kontrola MeSH
- inhibitory agregace trombocytů farmakologie terapeutické užití MeSH
- kardiovaskulární nemoci mortalita prevence a kontrola MeSH
- klinické zkoušky jako téma MeSH
- krvácení chemicky indukované MeSH
- lidé MeSH
- primární prevence metody statistika a číselné údaje MeSH
- rizikové faktory kardiovaskulárních chorob * MeSH
- Check Tag
- lidé MeSH
AIMS: Granulation tissue (GT) and specialized pro-resolving mediators such as lipoxins and resolvins are key elements in the successful resolution of periodontitis. Aspirin-triggered lipoxins and resolvins are even more powerful than their natural analogues. Their biosynthesis can be accelerated by omega-3 fatty acids. The aim of this study was to evaluate the use of GT enriched by aspirin and omega-3 fatty acids during the surgical treatment of periodontitis in an experimental animal model (rabbit). METHODS: In each of 24 rabbits, two experimental periodontal defects were created. In total, 47 defects were treated with open-flap debridement and one of three procedures: (1) GT extracted and soaked with aspirin and omega-3 fatty acids (ASA+OMEGA3 group); (2) GT soaked with saline (PLACEBO group); or (3) GT left untreated (CONTROL group). Then, the GT was replaced in situ. Primary evaluated criteria were the probing pocket depth (PPD) and the clinical attachment level (CAL). Necropsies were harvested 2, 6, and 12 weeks after surgery. The samples were used for histological and molecular biological assessment. RESULTS: A trend of greater PPD and CAL in the ASA+OMEGA3 group was observed at 6 weeks. However, there was no significant difference between them. During the observation period, tissue levels of FGF-7, IL-1β and TIMP-1 showed a statistically significant decrease (P<0.05). For the other variables, the ASA+OMEGA3 group was comparable with the PLACEBO and CONTROL groups. CONCLUSION: This experiment did not demonstrate the superiority of the proposed approach. However, the enriched granulation tissue did not impair healing outcomes.
- MeSH
- Aspirin farmakologie MeSH
- granulační tkáň MeSH
- králíci MeSH
- kyseliny mastné omega-3 * farmakologie MeSH
- lipoxiny * MeSH
- parodontitida * farmakoterapie MeSH
- tuberkulin MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Akutní infarkt myokardu vzniká nejčastěji na podkladě trombotického uzávěru koronární tepny, který nasedá na rupturu nestabilního aterosklerotického plátu. Klíčovým faktorem pro léčbu pacientů s infarktem myokardu je dosažení časné reperfuze infarktové tepny. K tomuto účelu slouží v dnešní době provedení primární perkutánní koronární intervence. U malé části pacientů, splňujících indikační kritéria, je možné podat trombolytickou léčbu. Součástí obou těchto výše uvedených reperfuzních modalit je antitrombotická terapie. Základní kámen léčby všech forem ischemické choroby srdeční, včetně akutního infarktu myokardu, představuje již dlouhou dobu kyselina acetylsalicylová (ASA). Neméně důležitou součástí je podání heparinu, a to buď nefrakcionovaného či nízkomolekulárního. Článek pojednává o iniciální léčbě pacientů s akutním infarktem myokardu s elevacemi ST úseků kyselinou acetylsalicylovou a hepariny a o jejich dávkování.
Acute myocardial infarction most commonly occurs as a result of a thrombotic occlusion of a coronary artery that originates as a consequence of an unstable atherosclerotic plaque rupture. Early reperfusion of the infarct related artery is a crucial factor in treating patients with myocardial infarction. For this purpose, primary percutaneous coronary intervention is currently performed. In a small proportion of patients meeting the indication criteria, it is possible to administer thrombolytic therapy. Antithrombotic therapy is a part of both these above-mentioned reperfusion modalities. Acetylsalicylic acid has long been the mainstay of treatment of all forms of ischaemic heart disease, including acute myocardial infarction. The administration of both unfractionated and low-molecular-weight heparin is of equal importance. The article deals with the initial treatment of acute ST-elevation myocardial infarction patients using acetylsalicylic acid and heparins and with its dosage.
- MeSH
- Aspirin * aplikace a dávkování farmakologie MeSH
- enoxaparin aplikace a dávkování MeSH
- heparin aplikace a dávkování MeSH
- infarkt myokardu s elevacemi ST úseků * farmakoterapie mortalita MeSH
- inhibitory agregace trombocytů aplikace a dávkování farmakologie MeSH
- kardiovaskulární nemoci farmakoterapie mortalita prevence a kontrola MeSH
- lidé MeSH
- reperfuze MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- MeSH
- Aspirin analýza farmakologie MeSH
- duální protidestičková léčba MeSH
- inhibitory agregace trombocytů * MeSH
- kardiologie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
