With an increasing focus on sustainable technologies in the pharmaceutical industry, milling provides a solvent-free approach to improve drug dissolution. Milling of drugs with an excipient offers additional opportunities to achieve supersaturation kinetics. Therefore, this work aims to present insights of co-milling fenofibrate and apremilast, two good glass formers with low and high glass transition temperatures (Tgs) respectively. Drugs were co-milled with croscarmellose sodium for various process durations followed by thermal analysis, investigation of crystallinity, surface area and dissolution. The dissolution enhancement of the low-Tg glass former fenofibrate highly correlated with the process-induced increase in surface area of co-milled systems (R2 = 0.96). In contrast, the high-Tg glass former apremilast lost its crystalline order gradually after ≥ 10 min of co-milling, and favourable supersaturation kinetics during biorelevant dissolution testing were observed. Interestingly, the melting point of co-milled apremilast decreased and linearly correlated with the highest measured drug concentration (cmax) during in vitro dissolution (onset temperature R2 = 0.98; peak temperature R2 = 0.96). The melting point depression remained stable after 90 days for apremilast, whereas fenofibrate co-milled for 20 min or more showed an increase in melting point upon storage. This study demonstrated that co-milling with croscarmellose sodium is ideally suited to good glass formers with a high Tg. The melting point depression is thereby proposed as an easily accessible critical quality attribute to estimate likely dissolution performance of drugs in dry co-milled formulations.

• Klíčová slova
• Ball milling, Co-milling, Croscarmellose sodium, Drug supersaturation, Glass forming ability, Glass transition temperature, Melting point depression,
• MeSH
• Aspirin chemie   analogy a deriváty   MeSH
• fenofibrát * chemie   MeSH
• pomocné látky chemie   MeSH
• příprava léků metody   MeSH
• rozpustnost MeSH
• sklo * chemie   MeSH
• thalidomid analogy a deriváty   MeSH
• tranzitní teplota MeSH
• uvolňování léčiv MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• apremilast MeSH Prohlížeč
• Aspirin MeSH
• fenofibrát * MeSH
• pomocné látky MeSH
• thalidomid MeSH

In the clinical evaluation of upper extremity embolism cases, the anamnesis should focus on identifying potential triggering risk factors. The physical examination may reveal sensory deficits, aiding in the determination of ischemia stages. Imaging diagnosis is crucial, with computed tomography (CT) angiography being the preferred examination due to its ability to provide detailed information about arterial anatomy across multiple planes and clear visualization of adjacent structures. Compared to magnetic resonance imaging angiography, CT angiography offers faster results with minimal distortion, despite the exposure to radiation and contrast use. Doppler ultrasonography is another valuable tool in suspected arterial thromboembolism cases, particularly in emergency settings. It offers advantages over CT angiography as it is non-invasive, cost-effective, and does not involve radiation or contrast administration. We present the case of a 68-year-old man who reported a nodule in the medial region of his right thumb for three months. Initially, he experienced significant local pain and limited movement, which gradually improved over time with the use of analgesic medication. Ultrasonography revealed thrombosis in the princeps pollicis artery, and the patient commenced treatment with acetylsalicylic acid. After four months, the patient reported a marked reduction in the nodule size along with pain improvement.

• Klíčová slova
• Doppler, Princeps pollicis artery, Thrombosis, Ultrasonography,
• MeSH
• Aspirin terapeutické užití   MeSH
• CT angiografie MeSH
• lidé MeSH
• palec ruky * krevní zásobení   MeSH
• senioři MeSH
• trombóza * diagnostické zobrazování   farmakoterapie   diagnóza   MeSH
• ultrasonografie dopplerovská MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• Aspirin MeSH

PURPOSE OF THE STUDY: Given the risk of venous thromboembolism (DVT) and pulmonary embolism (PE) after large joint replacement, the role of thromboprophylaxis is crucial. This retrospective study aims to evaluate the effectiveness of aspirin as thromboprophylaxis in patients undergoing TKA or THA. MATERIAL AND METHODS: In this retrospective review of a database of patients who underwent total hip and total knee replacements between 2021 and 2023, we divided patients into two groups: those with no anticoagulation therapy before surgery and those on chronic anticoagulant use prior to surgery. The primary endpoint was the number of patients with complications after aspirin use in the postoperative period. We collected patient demographic information, history of anticoagulant use, postoperative anticoagulant usage, comorbidities, type of surgery, reactions to anticoagulants, complications related to thromboembolism, length of hospital stay, and hospital readmissions. RESULTS: For patients who underwent elective THA or TKA, no significant difference in overall VTE or PE rates was detected when comparing aspirin with other anticoagulants. No mortality events were reported. However, there were differences in bleeding event rates between the aspirin group and other anticoagulant groups. CONCLUSIONS: Proper patient selection and early postoperative mobilization support the use of aspirin as a thromboprophylaxis therapy. The results of this study confirm that aspirin is a safe alternative to other anticoagulants in the postoperative management of THA and TKA.

• Klíčová slova
• aspirin, thromboprophylaxis, total hip arthroplasty, total knee arthroplasty,
• MeSH
• antikoagulancia terapeutické užití   aplikace a dávkování   MeSH
• Aspirin * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• délka pobytu MeSH
• lidé středního věku MeSH
• lidé MeSH
• náhrada kyčelního kloubu * škodlivé účinky   MeSH
• plicní embolie * prevence a kontrola   etiologie   epidemiologie   MeSH
• pooperační komplikace * prevence a kontrola   epidemiologie   etiologie   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• totální endoprotéza kolene * škodlivé účinky   MeSH
• žilní tromboembolie * prevence a kontrola   etiologie   epidemiologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• antikoagulancia MeSH
• Aspirin * MeSH

IMPORTANCE: The Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart Failure (ARIES-HM3) study demonstrated that aspirin may be safely eliminated from the antithrombotic regimen after HeartMate 3 (HM3 [Abbott Cardiovascular]) left ventricular assist device (LVAD) implantation. This prespecified analysis explored whether conditions requiring aspirin (prior percutaneous coronary intervention [PCI], coronary artery bypass grafting [CABG], stroke, or peripheral vascular disease [PVD]) would influence outcomes differentially with aspirin avoidance. OBJECTIVE: To analyze aspirin avoidance on hemocompatibility-related adverse events (HRAEs) at 1 year after implant in patients with a history of CABG, PCI, stroke, or PVD. DESIGN, SETTING, AND PARTICIPANTS: This was an international, multicenter, prospective, double-blind, placebo-controlled, randomized clinical trial including patients implanted with a de novo HM3 LVAD across 51 centers. Data analysis was conducted from April to July 2024. INTERVENTIONS: Patients were randomized in a 1:1 ratio to receive aspirin (100 mg per day) or placebo, in addition to a vitamin K antagonist (VKA) targeted to an international normalized ratio of 2 to 3 in both groups. MAIN OUTCOMES AND MEASURES: Primary end point (assessed for noninferiority) was a composite of survival free of any nonsurgical (>14 days after implant) HRAEs including stroke, pump thrombosis, bleeding, and arterial peripheral thromboembolism at 12 months. Secondary end points included nonsurgical bleeding, stroke, and pump thrombosis events. RESULTS: Among 589 of 628 patients (mean [SD] age, 57.1 [13.7] years; 456 male [77.4%]) who contributed to the primary end point analysis, a history of PCI, CABG, stroke, or PVD was present in 41% (240 of 589 patients). There was no interaction between the presence of an atherosclerotic vascular condition and effect of aspirin compared with placebo (P for interaction= .23). The preset 10% noninferiority margin was not crossed for the studied subgroup of patients. Thrombotic events were rare, with no differences between aspirin and placebo in patients with and without vascular disease (P for interaction = .77). Aspirin treatment was associated with a higher rate of nonsurgical major bleeding events in the group with prior vascular condition history compared with those without aspirin (rate ratio for placebo compared with aspirin, 0.52; 95% CI, 0.35-0.79). CONCLUSIONS AND RELEVANCE: Results of this prespecified analysis of the ARIES-HM3 randomized clinical trial demonstrate that in patients with advanced heart failure who have classical indications for antiplatelet therapy use at the time of LVAD implantation, aspirin avoidance was safe and not associated with increased thrombosis risk. Importantly, elimination of aspirin was associated with no increased thrombosis but a reduction in nonsurgical bleeding events in patients with a history of PCI, CABG, stroke, or PVD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04069156.

• MeSH
• Aspirin * aplikace a dávkování   MeSH
• ateroskleróza * komplikace   MeSH
• cévní mozková příhoda MeSH
• dvojitá slepá metoda MeSH
• fibrinolytika terapeutické užití   MeSH
• inhibitory agregace trombocytů * terapeutické užití   MeSH
• koronární angioplastika MeSH
• krvácení chemicky indukované   MeSH
• lidé středního věku MeSH
• lidé MeSH
• podpůrné srdeční systémy * škodlivé účinky   MeSH
• prospektivní studie MeSH
• sekundární analýza dat MeSH
• senioři MeSH
• srdeční selhání * terapie   chirurgie   komplikace   MeSH
• trombóza prevence a kontrola   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• komentáře MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• Aspirin * MeSH
• fibrinolytika MeSH
• inhibitory agregace trombocytů * MeSH

BACKGROUND: Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD. OBJECTIVES: We hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime. METHODS: A cohort of stable CVD patients (N = 40) who participated in the COMPASS trial and were previously randomized to receive aspirin were prospectively recruited and assigned a revised regimen of open-label aspirin plus rivaroxaban. Blood samples were obtained at baseline (aspirin only) and 6-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis. RESULTS: The COMPASS regime fundamentally altered small (<200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up. CONCLUSION: The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.

• Klíčová slova
• aspirin, cardiovascular disease, extracellular vesicles, proteomics, rivaroxaban,
• MeSH
• Aspirin * aplikace a dávkování   škodlivé účinky   MeSH
• biologické markery krev   MeSH
• časové faktory MeSH
• dvojitá slepá metoda MeSH
• extracelulární vezikuly * metabolismus   účinky léků   MeSH
• fibrinolytika * aplikace a dávkování   škodlivé účinky   MeSH
• inhibitory agregace trombocytů * aplikace a dávkování   škodlivé účinky   MeSH
• inhibitory faktoru Xa * aplikace a dávkování   škodlivé účinky   MeSH
• kardiovaskulární nemoci * krev   farmakoterapie   diagnóza   MeSH
• kombinovaná farmakoterapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mediátory zánětu * krev   MeSH
• prospektivní studie MeSH
• proteomika MeSH
• rivaroxaban * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• trombóza * krev   prevence a kontrola   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• Aspirin * MeSH
• biologické markery MeSH
• fibrinolytika * MeSH
• inhibitory agregace trombocytů * MeSH
• inhibitory faktoru Xa * MeSH
• mediátory zánětu * MeSH
• rivaroxaban * MeSH

The influenza RNA-dependent RNA polymerase harbours an endonuclease subunit characterized by a catalytic site housing two divalent metal ions. By effectively chelating both Mg2+ and Mn2+ ions, a small-molecule inhibitor with a metal-binding pharmacophore can halt endonuclease activity. Herein, two 3'-dehydroxypurpurogallin-4-carboxamide series, namely twelve C-4' unsubstituted and twelve C-4' phenyl substituted congeners were designed and prepared to be tested as inhibitors of the metal-dependent viral enzyme. These inhibitors were accessed through the chemoenzymatic reaction of gallic acid with either pyrocatechol or phenylpyrocatechol moderated by laccase, followed by amidation. Experimental IC50 values were determined using AlphaScreen technology, with the most potent inhibitors exhibiting IC50 values around 0.35 μM. Using X-ray crystallography, we analyzed structure of the endonuclease in complex with one potent 3'-dehydroxypurpurogallin-carboxamide at 2.0 Å resolution, revealing the coordination of the compound's triad of oxygen atoms with the two metal ions in the influenza A endonuclease active site.

• Klíčová slova
• Chemical synthesis, Endonuclease, Enzyme inhibition, Influenza, Metalloenzymes,
• MeSH
• amidy * chemie   farmakologie   chemická syntéza   MeSH
• antivirové látky * chemická syntéza   farmakologie   chemie   MeSH
• endonukleasy * antagonisté a inhibitory   metabolismus   MeSH
• inhibitory enzymů * chemická syntéza   chemie   farmakologie   MeSH
• krystalografie rentgenová MeSH
• kyselina gallová * chemie   farmakologie   analogy a deriváty   chemická syntéza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• virus chřipky A * enzymologie   účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amidy * MeSH
• antivirové látky * MeSH
• endonukleasy * MeSH
• inhibitory enzymů * MeSH
• kyselina gallová * MeSH

Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cenocepacia are considered emerging pathogens classified as a public health problem due to extensive antimicrobial resistance. Therefore, the discovery of new therapeutic strategies has become crucial. This study aimed to evaluate the antimicrobial activity of gallic acid and methyl gallate against non-fermenting bacteria. The study included five clinical isolates of Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cenocepacia. The minimum inhibitory concentrations of gallic acid and methyl gallate were determined by the broth microdilution method. Growth curves, metabolic activity, and biofilm formation of each bacterial strain in the presence or absence of phenolic compounds were performed. Finally, the therapeutic efficacy of the compounds was evaluated using an in vivo model. Gallic acid and methyl gallate showed antibacterial activity against bacterial strains in a concentration range of 64 to 256 µg/mL, both compounds reduced bacterial growth and metabolic activity of the strains, even at subinhibitory concentrations. Only, methyl gallate exhibited activity to inhibit the formation of bacterial biofilms. Moreover, gallic acid and methyl gallate increased larval survival by up to 60% compared to 30% survival of untreated larvae in a bacterial infection model in Galleria mellonella. Our results highlight the potential of gallic acid and methyl gallate as therapeutic alternatives for infections by emerging non-fermentative bacteria.

• Klíčová slova
• Achromobacter xylosoxidans, Burkholderia cenocepacia, Stenotrophomonas maltophilia, Antimicrobial activity, Phenolic compounds,
• MeSH
• antibakteriální látky * farmakologie   MeSH
• biofilmy účinky léků   růst a vývoj   MeSH
• gramnegativní bakteriální infekce mikrobiologie   farmakoterapie   MeSH
• kyselina gallová * farmakologie   analogy a deriváty   MeSH
• larva mikrobiologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• můry mikrobiologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky * MeSH
• kyselina gallová * MeSH
• methyl gallate MeSH Prohlížeč

The antioxidant activity of Scorzonera parviflora Jacq. roots were assessed by measuring their ability to scavenge ABTS and DPPH radicals. Bioactivity-guided fractionation was utilized to identify the compound(s) responsible for this activity. The most active phase, ethyl acetate, was isolated using column chromatography. The resulting fractions were then purified using preparative TLC on reverse phase and semi-preparative HPLC. The structures of the pure compounds were elucidated by spectral analysis (MS and 1H, 13C, 2D-NMR). Three undescribed phenolic acid derivatives, namely parvifloric acid A (1), B (2), and C (3), and one new sesquiterpene lactone, parviflorin (4) together with seven known compounds were isolated and identified as scopolin (5), scopoletin (6), caffeic acid (7), protocatechuic acid (8), 4,5-O-dicaffeoylquinic acid (9) 3,5-O-dicaffeoylquinic acid (10), and 3,5-O-dicaffeoylquinic acid methyl ester (11). Finally, the pure compounds obtained were tested to evaluate their antioxidant capacities, using ABTS and DPPH radical scavenging potencies. The highest activity was observed with 3,5-O-dicaffeoylquinic acid (10), followed by its methyl ester.

• Klíčová slova
• Antioxidant activity, Asteraceae, Phenolic acids, Scorzonera parviflora, Sesquiterpene lactone,
• MeSH
• antioxidancia * farmakologie   izolace a purifikace   chemie   MeSH
• fytonutrienty farmakologie   izolace a purifikace   MeSH
• hydroxybenzoáty * izolace a purifikace   farmakologie   chemie   MeSH
• kořeny rostlin * chemie   MeSH
• molekulární struktura MeSH
• Scorzonera * chemie   MeSH
• seskviterpeny farmakologie   izolace a purifikace   chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antioxidancia * MeSH
• fytonutrienty MeSH
• hydroxybenzoáty * MeSH
• phenolic acid MeSH Prohlížeč
• seskviterpeny MeSH

The valence and core electronic structure of three non-steroidal anti-inflammatory drugs (methyl salicylate, fenoprofen and ketoprofen) have been studied by photoelectron and soft X-ray absorption spectroscopy, supported by theoretical calculations of the molecular and electronic structure. The conformational landscape has been explored for sixteen low-energy conformers of fenoprofen and ketoprofen, and the energies of both compounds fall into two groups with steric similarities, separated by about 3 kJ mol-1. Valence band photoelectron spectra agree with previous results, and the spectra have been calculated using two approaches. We find the outer valence Green's function method gives good results, but the P3+ method is a little better, particularly for outer valence ionic states. Carbon and oxygen 1s photoemission spectra are reported and are in acceptable agreement with the theory. The C and O K near-edge X-ray absorption fine structure spectra are reported and interpreted by comparison with reference compounds. We analyse the data to provide rough estimates of the energies of the unoccupied orbitals in methyl salicylate.

• MeSH
• antiflogistika nesteroidní * chemie   MeSH
• elektrony MeSH
• fenoprofen * chemie   MeSH
• fotoelektronová spektroskopie MeSH
• ketoprofen * chemie   MeSH
• molekulární konformace MeSH
• molekulární struktura MeSH
• plyny chemie   MeSH
• rentgenová absorpční spektroskopie MeSH
• salicylany * chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antiflogistika nesteroidní * MeSH
• fenoprofen * MeSH
• ketoprofen * MeSH
• methyl salicylate MeSH Prohlížeč
• plyny MeSH
• salicylany * MeSH

The effective treatment of inflammatory diseases, particularly their chronic forms, is a key task of modern medicine. Herein, we report the synthesis and evaluation of biocompatible polymer conjugates based on N-2-(hydroxypropyl)methacrylamide copolymers enabling the controlled release of acetylsalicylic acid (ASA)-based anti-inflammatory drugs under specific stimuli. All polymer nanotherapeutics were proposed as water-soluble drug delivery systems with a hydrodynamic size below 10 nm ensuring suitability for the parenteral application and preventing opsonization by the reticuloendothelial system. The nanotherapeutics bearing an ester-bound ASA exhibited long-term release of the ASA/salicylic acid mixture, while the nanotherapeutics carrying salicylic acid hydrazide (SAH) ensured the selective release of SAH in the acidic inflammatory environment thanks to the pH-sensitive hydrazone bond between the polymer carrier and SAH. The ASA- and SAH-containing nanotherapeutics inhibited both cyclooxygenase isoforms and/or the production of pro-inflammatory mediators. Thanks to their favorable design, they can preferentially accumulate in the inflamed tissue, resulting in reduced side effects and lower dosage, and thus more effective and safer treatment.

• Klíčová slova
• Acetylsalicylic acid, Drug delivery, HPMA, Inflammation, Nanotherapeutics, Salicylic acid hydrazide,
• MeSH
• akrylamidy chemie   farmakologie   aplikace a dávkování   MeSH
• antiflogistika farmakologie   aplikace a dávkování   chemie   MeSH
• Aspirin * aplikace a dávkování   farmakologie   chemie   MeSH
• cyklooxygenasy metabolismus   MeSH
• inhibitory cyklooxygenasy farmakologie   aplikace a dávkování   chemie   MeSH
• léky s prodlouženým účinkem * MeSH
• mediátory zánětu metabolismus   MeSH
• myši MeSH
• nanočástice * chemie   MeSH
• nosiče léků chemie   MeSH
• polymery * chemie   aplikace a dávkování   MeSH
• uvolňování léčiv MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• akrylamidy MeSH
• antiflogistika MeSH
• Aspirin * MeSH
• cyklooxygenasy MeSH
• inhibitory cyklooxygenasy MeSH
• léky s prodlouženým účinkem * MeSH
• mediátory zánětu MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
• nosiče léků MeSH
• polymery * MeSH