Regadenoson je selektivního A2A adenosin umožňující farmakologicky zatížit pacienty, u nichž by fyzická zátěž byla nemožná nebo jen velmi obtížná. Jsou prezentovány dvě kazuistiky demonstrující výhody tohoto preparátu. V prvním případě jsme se u 77letého muže po aortokoronárním bypassu nejprve pokoušeli o fyzickou zátěž, která byla pro nedostatečný vzestup tepové frekvence ihned změněna na zátěž farmakologickou. Během pokračující nižší úrovně fyzické zátěže byl aplikován regadenoson. Jednofotonová emisní tomografie (SPECT) zobrazila rozsáhlou ischemii laterální stěny a koronarografie následně prokázala uzávěr žilního štěpu na ramus circumflexus. Druhá kazuistika demonstruje současný pokrok technologie SPECT. Na moderních multidetektorových kadmium zinek telluridových (Cadmium Zinc Telluride, CZT) kamerách lze nahrávat dynamicky a kvantifikovat koronární průtokovou rezervu (coronary flow reserve, CFR), což může pomoci při identifikaci nemoci více koronárních tepen nebo mikrovaskulární ischemie. CFR se stanovuje jako poměr myokardiálního průtoku po vazodilataci navozené farmakologickou zátěži a v klidu. 50letý diabetik má na konvenčním SPECT myokardu normální pozátěžovou perfuzi i funkci levé komory. Dynamický SPECT prokázal normální hodnoty myokardiálního krevního průtoku (myocardial blood flow, MBF) i normální CFR ≥ 2. Během 18 měsíců sledování jsme u něj nezaznamenali kardiální příhodu.

Regadenoson as a selective A2A adenosine enables pharmacological stress when exercise stress techniques would be impossible or very difficult. We present two case reports demonstrating its advantages. In case 1, we initially attempted to induce stress using physical exercise in a 77-year-old male patient after coronary artery bypass graft. Due to inadequate heart rate increase, the stress was promptly converted to pharmacological stress using regadenoson in combination with a low level of exercise. Single-photon emission computed tomography (SPECT) showed extensive ischaemia of the lateral wall. Coronary angiography subsequently revealed vein graft occlusion at the left circumflex artery. Case 2 demonstrates recent advances in SPECT technology. Modern multidetector Cadmium Zinc Telluride (CZT) cameras enable dynamic acquisition and quantification of coronary flow reserve (CFR). It can be helpful in identifying multivessel disease or microvascular ischaemia. CFR is calculated as the ratio between myocardial blood flow during stress vasodilator hyperaemia and flow at rest. In a 50-year-old diabetic patient, a conventional cardiac SPECT showed normal post-stress left ventricular perfusion and function. Dynamic SPECT showed normal myocardial blood flow (MBF) and normal CFR ≥ 2. During 18 months of follow-up, no cardiac event was observed in this patient.

• Klíčová slova
• regadenoson,
• MeSH
• agonisté adenosinového receptoru A2 MeSH
• jednofotonová emisní výpočetní tomografie * metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• vazodilatancia MeSH
• zátěžový test metody   MeSH
• zobrazování myokardiální perfuze metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• kazuistiky MeSH

Rheumatoid arthritis (RA) is a chronic autoimmune disease with significant morbidity and mortality. Recent studies suggest that modulation of adenosine signaling, a potent immunosuppressive pathway, is a promising approach for treatment of RA. Extracellular adenosine can come from two sources: transport of intracellular adenosine and hydrolysis of extracellular adenine nucleotides by CD73. In this study, we investigated the susceptibility of CD73-deficient C57BL/6 mice to collagen-induced arthritis (CIA), a well-established mouse model of RA. Our data demonstrated that CD73-deficient mice are significantly more susceptible to CIA than wild-type mice. CD73 deficiency resulted in an increased production of proinflammatory cytokines in the joints, increased Th1 T cell responses, and increased joint destruction. Surprisingly, this was accompanied by delayed anticollagen IgG responses, suggesting defective isotype class switching in CD73-deficient mice. Using bone marrow chimera mice, we demonstrated that CD73 expression on nonhematopoietic cells, but not on hematopoietic cells, was important for protection from CIA. We further demonstrated that administration of a selective A2A adenosine receptor agonist to CD73-deficient mice resulted in arthritis incidence similar to wild-type mice in support of a protective role for A2A signaling. Taken together, our study identifies CD73 as an important regulator of CIA in mice. It also strengthens the notion that CD73-generated adenosine by nonhematopoietic cells plays a protective role in RA and suggests that strategies able to enhance CD73 activity or expression levels may be a valid therapeutic option.

• MeSH
• 5'-nukleotidasa nedostatek   genetika   imunologie   MeSH
• adenosin analogy a deriváty   farmakologie   MeSH
• agonisté adenosinového receptoru A2 farmakologie   MeSH
• artritida experimentální genetika   imunologie   prevence a kontrola   MeSH
• CD4-pozitivní T-lymfocyty imunologie   metabolismus   MeSH
• cytokiny imunologie   metabolismus   MeSH
• ELISA MeSH
• fenethylaminy farmakologie   MeSH
• imunoglobulin G imunologie   MeSH
• interferon gama imunologie   metabolismus   MeSH
• klouby imunologie   metabolismus   patologie   MeSH
• kolagen typ II imunologie   MeSH
• kur domácí MeSH
• lymfatické uzliny imunologie   metabolismus   MeSH
• mediátory zánětu imunologie   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• náchylnost k nemoci imunologie   MeSH
• odolnost vůči nemocem genetika   imunologie   MeSH
• ptačí proteiny imunologie   MeSH
• Th1 buňky imunologie   metabolismus   MeSH
• transplantace kostní dřeně MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• Brilique, studie PEGASUS-TIMI 54,
• MeSH
• adenosin analogy a deriváty   aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• agonisté purinergního receptoru P1 farmakologie   terapeutické užití   MeSH
• Aspirin aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• cévní mozková příhoda farmakoterapie   prevence a kontrola   MeSH
• infarkt myokardu farmakoterapie   prevence a kontrola   MeSH
• kardiovaskulární nemoci * farmakoterapie   prevence a kontrola   MeSH
• klinická studie jako téma MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• sekundární prevence MeSH
• ticagrelor MeSH
• Check Tag
• lidé MeSH

There exists a requirement for drugs which would be useful in therapy of an acute radiation damage of a mammalian organism. The aim of the study was to evaluate survival parameters in mice exposed to a lethal γ-ray dose of 8.5 Gy and treated with single doses of an adenosine A(3) receptor agonist, IB-MECA, or a cyclooxygenase-2 (COX-2) inhibitor, meloxicam, administered alone or in a combination early after irradiation, i.e., 0.5 and 1 h post-irradiation, respectively. The assessed parameters were the mean survival time (MST) and the cumulative percentage 30-day survival (CPS). Administrations of single intraperitoneal doses of either IB-MECA 0.5 h post-irradiation or meloxicam 1 h post-irradiation resulted in statistically significant increases of MST in comparison with the control irradiated mice. Combined administration of IB-MECA and meloxicam was found to be the only treatment statistically enhancing the parameter of CPS and to lead to the most expressive increase in MST of the experimental mice. The findings add new knowledge on the action of an adenosine A3 receptor agonist and a COX-2 inhibitor in an irradiated mammalian organism and suggest the potential of both the investigated drugs in the treatment of the acute radiation damage.

• MeSH
• adenosin analogy a deriváty   farmakologie   MeSH
• agonisté adenosinového receptoru A3 farmakologie   MeSH
• časové faktory MeSH
• celotělové ozáření škodlivé účinky   MeSH
• cyklooxygenasa 2 metabolismus   MeSH
• inhibitory cyklooxygenasy 2 farmakologie   MeSH
• lékové interakce MeSH
• míra přežití MeSH
• myši MeSH
• radioprotektivní látky farmakologie   MeSH
• receptor adenosinový A3 metabolismus   MeSH
• thiaziny farmakologie   MeSH
• thiazoly farmakologie   MeSH
• záření gama škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Adenosine plays an important role during inflammation, particularly through modulation of monocyte function. The objective of the present study was to evaluate the effect of synthetic adenosine analogs on cytokine production by porcine monocytes. The LPS-stimulated cytokine production was measured by flow cytometry and quantitative real-time PCR. Adenosine receptor expression was measured by quantitative real-time PCR. The present study demonstrates that adenosine analog N-ethylcarboxyamidoadenosine (NECA) down-regulates TNF-α production and up-regulates IL-8 production by LPS-stimulated porcine monocytes. The effect was more pronounced in CD163(-) subset of monocytes compared to the CD163(+) subset. Although both monocyte subsets express mRNA for A1, A2A, A2B and A3 adenosine receptors, the treatment of monocytes with various adenosine receptor agonists and antagonists proved that the effect of adenosine is mediated preferentially via A2A adenosine receptor. Moreover, the study suggests that the effect of NECA on porcine monocytes alters the levels of the cytokines which could play a role in the differentiation of naive T cells into Th17 cells. The results suggest that adenosine plays an important role in modulation of cytokine production by porcine monocytes.

• MeSH
• adenosin-5'-(N-ethylkarboxamid) farmakologie   MeSH
• adenosin farmakologie   MeSH
• agonisté purinergního receptoru P1 farmakologie   MeSH
• antagonisté purinergního receptoru P1 farmakologie   MeSH
• antigeny diferenciační myelomonocytární metabolismus   MeSH
• CD antigeny metabolismus   MeSH
• cytokiny biosyntéza   genetika   MeSH
• lipopolysacharidy farmakologie   MeSH
• messenger RNA genetika   metabolismus   MeSH
• monocyty účinky léků   metabolismus   MeSH
• purinergní receptory P1 genetika   metabolismus   MeSH
• receptory buněčného povrchu metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• Sus scrofa metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The question as to whether A3 adenosine receptor (A3AR) agonists, N (6)-(3-iodobenzyl)-adenosine-5'-N- methyluronamide (IB-MECA) and 2-chloro-N (6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), could exert cytotoxic effects at high concentrations with or without the involvement of A3AR has been a controversial issue for a long time. The initial findings suggesting that A3AR plays a crucial role in the induction of cell death upon treatment with micromolar concentrations of IB-MECA or Cl-IB-MECA were revised, however, the direct and unequivocal evidence is still missing. Therefore, the sensitivity of Chinese hamster ovary (CHO) cells transfected with human recombinant A3AR (A3-CHO) and their counter partner wild-type CHO cells, which do not express any of adenosine receptors, to micromolar concentrations of IB-MECA and Cl-IB-MECA was studied. We observed that IB-MECA and Cl-IB-MECA exhibited a strong inhibitory effect on cell proliferation due to the blockage of cell cycle progression at G1/S and G2/M transitions in both A3-CHO and CHO cells. Further analysis revealed that IB-MECA and Cl-IB-MECA attenuated the Erk1/2 signalling irrespectively to A3AR expression. In addition, Cl-IB-MECA induced massive cell death mainly with hallmarks of a necrosis in both cell lines. In contrast, IB-MECA affected cell viability only slightly independently of A3AR expression. IB-MECA induced cell death that exhibited apoptotic hallmarks. In general, the sensitivity of A3-CHO cells to micromolar concentrations of IB-MECA and Cl-IB-MECA was somewhat, but not significantly, higher than that observed in the CHO cells. These results strongly suggest that IB-MECA and Cl-IB-MECA exert cytotoxic effects at micromolar concentrations independently of A3AR expression.

• MeSH
• adenosin analogy a deriváty   farmakologie   MeSH
• agonisté adenosinového receptoru A3 farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• cytotoxiny farmakologie   MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• lidé MeSH
• mitogenem aktivovaná proteinkinasa 1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• mitogenem aktivovaná proteinkinasa 3 antagonisté a inhibitory   genetika   metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• protoonkogenní proteiny c-akt genetika   metabolismus   MeSH
• receptor adenosinový A3 genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• signální transdukce účinky léků   MeSH
• transfekce MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Prezentujeme dvě kazuistiky dokumentující výhody využití selektivního A2A adenozinu (regadenoson) při zátěžových testech v nukleární kardiologii, kdy zátěž konvenčními technikami by byla nemožná nebo jen velmi obtížná. V prvním případě jsme u 59leté diabetičky po infarktu léčeném přímou angioplastikou zobrazili pomocí jednofotonové emisní tomografie (SPECT) kvantitativně rozsáhlou ischemii v povodí infarktové tepny. Rekoronarografie prokázala in-stent restenózu a bylo zvoleno kardiochirurgické řešení. V druhé kazuistice měl 55letý polymorbidní pacient již v minulosti prokázán uzávěr v povodí ramus circumflexus léčený konzervativně. Nyní byl odeslán na SPECT pro atypické bolesti na hrudi. Zátěžový test prokázal jen mírnou ischemii a byla opět doporučena konzervativní strategie.

We present two case reports, demonstrating advantages of selective A2A adenosine (regadenoson) for use as a stress test in nuclear cardiology, when conventional stress techniques may be impossible or very difficult. In the case 1, 59-year-old diabetic female patient with a history of prior myocardial infarction was treated by direct angioplasty. Single-photon emission computed tomography (SPECT) showed quantitative extent ischemia in the territory of infarcted vessel. Repeated coronary angiography revealed in-stent restenosis and patient underwent bypass graft surgery. In the case 2, 55-year-old male, with several co-morbidities, had a history of conservative treatment of the occlusion of the left circumflex artery. At present, he was referred for SPECT because of atypical chest pain. Stress test showed a mild ischemia only and conservative strategy was recommended again.

• MeSH
• agonisté adenosinového receptoru A2 * aplikace a dávkování   farmakologie   metabolismus   MeSH
• chronická obstrukční plicní nemoc MeSH
• diabetes mellitus MeSH
• dyspnoe MeSH
• infarkt myokardu MeSH
• ischemie diagnóza   terapie   MeSH
• jednofotonová emisní výpočetní tomografie MeSH
• kardiologie * MeSH
• koronární cévy chirurgie   MeSH
• koronární restenóza MeSH
• lidé středního věku MeSH
• lidé MeSH
• morbidita MeSH
• nukleární lékařství * MeSH
• puriny aplikace a dávkování   farmakologie   metabolismus   MeSH
• pyrazoly aplikace a dávkování   farmakologie   metabolismus   MeSH
• radiofarmaka * farmakologie   MeSH
• radionuklidy MeSH
• srdeční frekvence MeSH
• zobrazování myokardiální perfuze MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

This study continues our earlier findings on the hematopoiesis-modulating effects of adenosine A1 and A3 receptor agonists that were performed on committed hematopoietic progenitor and precursor cell populations. In the earlier experiments, N (6)-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, was found to inhibit proliferation in the above-mentioned hematopoietic cell systems, whereas N (6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), an adenosine A3 receptor agonist, was found to stimulate it. The topic of this study was to evaluate the possibility that the above-mentioned adenosine receptor agonists modulate the behavior of early hematopoietic progenitor cells and hematopoietic stem cells. Flow cytometric analysis of hematopoietic stem cells in mice was employed, as well as a functional test of hematopoietic stem and progenitor cells (HSPCs). These techniques enabled us to study the effect of the agonists on both short-term repopulating ability and long-term repopulating ability, representing multipotent progenitors and hematopoietic stem cells, respectively. In a series of studies, we did not find any significant effect of adenosine agonists on HSPCs in terms of their numbers, proliferation, or functional activity. Thus, it can be concluded that CPA and IB-MECA do not significantly influence the primitive hematopoietic stem and progenitor cell pool and that the hematopoiesis-modulating action of these adenosine receptor agonists is restricted to more mature compartments of hematopoietic progenitor and precursor cells.

• MeSH
• agonisté purinergního receptoru P1 farmakologie   MeSH
• hematopoetické kmenové buňky účinky léků   fyziologie   MeSH
• hematopoéza účinky léků   fyziologie   MeSH
• multipotentní kmenové buňky účinky léků   fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• průtoková cytometrie MeSH
• receptor adenosinový A1 metabolismus   MeSH
• receptor adenosinový A3 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In our previous studies, IB-MECA, an adenosine A(3) receptor agonist, was found to stimulate proliferation of hematopoietic progenitor and precursor cells in mice. This property of IB-MECA was considered to be responsible for its ability to support regeneration of suppressed hematopoiesis after irradiation with sublethal doses of γ-rays when the drug was given in a post-irradiation treatment regimen. This study was aimed at assessing the ability of IB-MECA to influence a 30-day survival of lethally irradiated mice. In a series of experiments, IB-MECA was administered following various lethal radiation doses in various numbers of drug doses and various administration routes. Though in some of these experiments a moderate increase in 30-day survival was observed in IB-MECA-treated mice, the differences in comparison with the controls were not significantly different. It can be inferred from these results and those of previous studies assessing the effects of IB-MECA after sublethal radiation doses that IB-MECA can probably influence only a substantially preserved hematopoiesis like that remaining after sublethal irradiation. Future studies should be aimed at evaluation of the abilities of IB-MECA to influence post-irradiation survival when administered as a part of combined treatment regimens.

• MeSH
• adenosin aplikace a dávkování   analogy a deriváty   farmakologie   MeSH
• agonisté adenosinového receptoru A3 aplikace a dávkování   farmakologie   MeSH
• experimentální radiační poranění metabolismus   mortalita   MeSH
• hematopoéza účinky léků   účinky záření   MeSH
• inbrední kmeny myší MeSH
• myši MeSH
• receptor adenosinový A3 metabolismus   MeSH
• záření gama MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We studied effects of 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA) on apoptosis induction in the K562/Dox cell line, which overexpressed P-glycoprotein (P-gp, ABCB1, MDR1). We found that the K562/Dox cell line was significantly more resistant to Cl-IB-MECA than the maternal cell line K562, which did not express P-gp. Although both cell lines expressed the A3 adenosine receptor (A3AR), cytotoxic effects of Cl-IB-MECA were not prevented by its selective antagonist MRS1523 (3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2 phenyl-4-propyl-3-pyridine carboxylate). Analysis of cell extracts revealed that the intracellular level of Cl-IB-MECA was significantly lower in the K562/Dox cell line than in the maternal cell line K562. The downregulation of P-gp expression using shRNA targeting ABCB1 gene led to increased intracellular level of Cl-IB-MECA and restored cell sensitivity to this drug. Similarly, valspodar (PSC-833), a specific inhibitor of P-gp, restored sensitivity of the K562/Dox cell line to Cl-IB-MECA with concomitant increase of intracellular level of Cl-IB-MECA in the resistant cell line, while it affected cytotoxicity of Cl-IB-MECA in the sensitive cell line only marginally. An enzyme based assay provided evidence for interaction of P-gp with Cl-IB-MECA. We further observed that cytotoxic effects of Cl-IB-MECA could be augmented by activation of extrinsic cell death pathway by Apo-2L (TRAIL) but not FasL or TNF-α. Our results revealed that Cl-IB-MECA induced an increase in expression of TRAIL receptors in K562 cells, which could sensitize cells to apoptosis induction via an extrinsic cell death pathway. Importantly, these effects were inversely related to P-gp expression. In addition, MRS1523 did not affect Cl-IB-MECA induced expression of TRAIL receptors.

• MeSH
• adenosin analogy a deriváty   farmakologie   MeSH
• adenosintrifosfatasy metabolismus   MeSH
• agonisté adenosinového receptoru A3 farmakologie   MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• buněčná smrt MeSH
• chemorezistence fyziologie   MeSH
• leukemie farmakoterapie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• P-glykoprotein genetika   metabolismus   MeSH
• receptor adenosinový A3 metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH