V současné době nová přímá perorální antikoagulancia (DOAC) postupně nahrazují dosavadní historicky nejčastěji užívaný warfarin. Jedná se o dvě skupiny léčiv přímo inhibující faktor Xa (Xarelto, Eliquis, Lixiana) a trombin (Pradaxa). Nabízí mnohá pozitiva, která ocení i samotní pacienti. Jedná se zejména o odpadnutí nutnosti pravidelné monitorace, minimum lékových a potravinových interakcí či příznivý bezpečnostní profil. Nicméně jako jednu z nevýhod lze vnímat nepřítomnost antidota při předávkování. Své specifické antidotum - Idarucizumab - má v současné době pouze Pradaxa. Ostatní jsou ve vývoji, stejně tak jako nové molekuly samotných antikoagulancií.

Currently, new direct oral anticoagulants (DOAC) are gradually replacing the historically most frequently used warfarin. These are two classes of drugs directly inhibiting factor Xa (Xarelto, Eliquis, Lixiana) and thrombin (Pradaxa). It offers many positives that patients themselves will appreciate. These include, in particular, no need for regular monitoring, minimal drug and food interactions, or afavorable safety profile. However, one of the drawbacks is the absence of antidotes for overdose. Only Pradaxa currently has its specific antidote - Idarucizumab. Others are in development as well as new molecules of anticoagulants themselves.

• Klíčová slova
• betrixaban, darexaban, otamixaban, andexanet, ciraparantag,
• MeSH
• antidota farmakologie   terapeutické užití   MeSH
• antikoagulancia * farmakokinetika   farmakologie   terapeutické užití   MeSH
• azepiny farmakokinetika   farmakologie   terapeutické užití   MeSH
• benzamidy farmakokinetika   farmakologie   terapeutické užití   MeSH
• cyklické N-oxidy farmakokinetika   farmakologie   terapeutické užití   MeSH
• faktor Xa analogy a deriváty   terapeutické užití   účinky léků   MeSH
• inhibitory faktoru Xa * farmakokinetika   farmakologie   terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• tromboembolie prevence a kontrola   MeSH
• Check Tag
• lidé MeSH

V současné době nová přímá perorální antikoagulancia (DOAC) postupně nahrazují dosavadní historicky nejčastěji užívaný warfarin. Jedná se o dvě skupiny léčiv přímo inhibující faktor Xa (Xarelto, Eliquis, Lixiana) a trombin (Pradaxa). Nabízí mnohá pozitiva, která ocení i samotní pacienti. Jedná se zejména o odpadnutí nutnosti pravidelné monitorace, minimum lékových a potravinových interakcí či příznivý bezpečnostní profil. Nicméně jako jednu z nevýhod lze vnímat nepřítomnost antidota při předávkování. Své specifické antidotum - Idarucizumab - má v současné době pouze Pradaxa. Ostatní jsou ve vývoji, stejně tak jako nové molekuly samotných antikoagulancií.

Currently, new direct oral anticoagulants (DOAC) are gradually replacing the historically most frequently used warfarin. These are two classes of drugs directly inhibiting factor Xa (Xarelto, Eliquis, Lixiana) and thrombin (Pradaxa). It offers many positives that patients themselves will appreciate. These include, in particular, no need for regular monitoring, minimal drug and food interactions, or afavorable safety profile. However, one of the drawbacks is the absence of antidotes for overdose. Only Pradaxa currently has its specific antidote - Idarucizumab. Others are in development as well as new molecules of anticoagulants themselves.

• Klíčová slova
• betrixaban, darexaban, otamixaban, andexanet, ciraparantag,
• MeSH
• antidota farmakologie   terapeutické užití   MeSH
• antikoagulancia * farmakokinetika   farmakologie   terapeutické užití   MeSH
• azepiny farmakokinetika   farmakologie   terapeutické užití   MeSH
• benzamidy farmakokinetika   farmakologie   terapeutické užití   MeSH
• cyklické N-oxidy farmakokinetika   farmakologie   terapeutické užití   MeSH
• faktor Xa analogy a deriváty   terapeutické užití   účinky léků   MeSH
• inhibitory faktoru Xa * farmakokinetika   farmakologie   terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• tromboembolie prevence a kontrola   MeSH
• Check Tag
• lidé MeSH

Obstructive sleep apnea (OSA) has been demonstrated to be implicated in disorder of insulin secretion and diabetes mellitus. In this study, we aimed to evaluate the protective role of tempol, a powerful antioxidant, in chronic intermittent hypoxia (IH)-induced pancreatic injury. The rat model of OSA was established by IH exposure. The pathological changes, increased blood-glucose level, and raised proinsulin/insulin ratio in pancreatic tissues of rats received IH were effectively relieved by tempol delivery. In addition, the enhanced levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta, IL-6, and inflammatory mediators, PGE2, cyclooxygenase-2 (COX-2), NO, and inducible nitric oxide synthase (iNOS) in pancreatic tissue were suppressed by tempol. Moreover, tempol inhibited IH-induced apoptosis in pancreatic tissue as evidenced by upregulated Bcl-2 level, and downregulated Bax and cleaved caspase-3 levels. Finally, the abnormal activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling pathways induced by IH was restrained by tempol administration. In summary, our study demonstrates that tempol relieves IH-induced pancreatic injury by inhibiting inflammatory response and apoptosis, which provides theoretical basis for tempol as an effective treatment for OSA-induced pancreatic injury.

• MeSH
• antioxidancia farmakologie   terapeutické užití   MeSH
• apoptóza účinky léků   fyziologie   MeSH
• cyklické N-oxidy farmakologie   terapeutické užití   MeSH
• hypoxie farmakoterapie   metabolismus   patologie   MeSH
• krysa rodu rattus MeSH
• mediátory zánětu antagonisté a inhibitory   metabolismus   MeSH
• obstrukční spánková apnoe farmakoterapie   metabolismus   patologie   MeSH
• pankreas účinky léků   metabolismus   patologie   MeSH
• potkani Wistar MeSH
• spinové značení MeSH
• zánět farmakoterapie   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Adaptation to chronic intermittent hypoxia (CIH) is associated with reactive oxygen species (ROS) generation implicated in the improved cardiac tolerance against acute ischemia-reperfusion injury. Phospholipases A2 (PLA2s) play an important role in cardiomyocyte phospholipid metabolism influencing membrane homeostasis. Here we aimed to determine the effect of CIH (7000 m, 8 h/day, 5 weeks) on the expression of cytosolic PLA2 (cPLA2α), its phosphorylated form (p-cPLA2α), calcium-independent (iPLA2), and secretory (sPLA2IIA) at protein and mRNA levels, as well as fatty acids (FA) profile in left ventricular myocardium of adult male Wistar rats. Chronic administration of antioxidant tempol was used to verify the ROS involvement in CIH effect on PLA2s expression and phospholipid FA remodeling. While CIH did not affect PLA2s mRNA levels, it increased the total cPLA2α protein in cytosol and membranes (by 191% and 38%, respectively) and p-cPLA2α (by 23%) in membranes. On the contrary, both iPLA2 and sPLA2IIA were downregulated by CIH. CIH further decreased phospholipid n-6 polyunsaturated FA (PUFA) and increased n-3 PUFA proportion. Tempol treatment prevented only CIH-induced cPLA2α up-regulation and its phosphorylation on Ser505. Our results show that CIH diversely affect myocardial PLA2s and suggest that ROS are responsible for the activation of cPLA2α under these conditions.

• MeSH
• antioxidancia farmakologie   MeSH
• chronická nemoc MeSH
• cyklické N-oxidy farmakologie   MeSH
• fosfolipasy A2, skupina IV genetika   metabolismus   MeSH
• fosforylace účinky léků   MeSH
• hypoxie enzymologie   metabolismus   MeSH
• krysa rodu rattus MeSH
• mastné kyseliny metabolismus   MeSH
• potkani Wistar MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• regulace genové exprese enzymů účinky léků   MeSH
• spinové značení MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Two mechanisms contribute in the development of pulmonary hypertension in pulmonary embolism (PE) - obstruction of pulmonary blood vessels and vasoconstriction. We hypothesize that hypoxia, increased shear stress and/or activation of gathered leukocytes in the PE may cause a release of reactive oxygen species (ROS). Therefore our aim was to determine the influence of the ROS scavenger Tempol on pulmonary hypertension and to describe NO synthase activity and production of NO oxidative products (NOx) after PE. In general anesthesia sephadex microspheres suspended in PSS were applied in right jugular vein as the pulmonary microembolism. Than we measured in isolated salt solution-perfused lungs the changes in perfusion pressure, activity of NO synthase and NOx plasma concentration in 7 groups of rats: C: control group (n=5), CN: C + sodium nitroprusside (SN) (n=5), EN: PE + SN (n=5), ETN: Tempol + PE + SN (n=5), CL: C + L-NAME (n=5), EL: PE + L-NAME (n=5), ETL: Tempol + PE + L-NAME (n=5). Tempol was applied intraperitoneally before PE. Animals that received Tempol (groups TN, TL) had significantly lower basal perfusion pressure than those which did not receive Tempol (EN, EL). Overall we measured a higher decrease of perfusion pressure than in the control group (C) after application of SN. Administration of L-NAME after PE (EL) increased the pressure more than in the control group (NL). NOx concentration was higher after PE. We found that preventive administration of Tempol decreases the increase in perfusion pressure after PE. PE increased NO release and concentration of NOx.

• MeSH
• aktivace enzymů účinky léků   fyziologie   MeSH
• cyklické N-oxidy farmakologie   terapeutické užití   MeSH
• krevní tlak účinky léků   fyziologie   MeSH
• krysa rodu rattus MeSH
• mikrocirkulace účinky léků   fyziologie   MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• orgánové kultury - kultivační techniky MeSH
• plicní embolie farmakoterapie   metabolismus   MeSH
• plicní oběh účinky léků   fyziologie   MeSH
• potkani Wistar MeSH
• reaktivní formy kyslíku antagonisté a inhibitory   metabolismus   MeSH
• scavengery volných radikálů farmakologie   terapeutické užití   MeSH
• spinové značení MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   metabolismus   MeSH
• vazokonstrikce účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIM: It is well-known that salt hypertension is associated with increased oxidative stress. Since the development of salt hypertension is age-dependent, we were interested whether young and adult salt hypertensive Dahl rats differ in oxidative stress level and/or in the effects of chronic antioxidant therapy on blood pressure (BP) level and on the participation of particular vasoconstrictor/vasodilator systems in BP maintenance. METHODS: Young (5-week-old) and adult (12-week-old) salt-sensitive (Dahl-S) male rats were fed high-salt diet (5% NaCl) and drank tempol solution (2 mm) for 5 weeks. BP was monitored with radiotelemetry and vasoconstrictor/vasodilator balance was evaluated at the end of experiment. Moreover, NO synthase activity, superoxide production and lipoperoxidation were determined in heart, kidney and aorta in separate subgroups of Dahl rats. RESULTS: Tempol treatment had quite opposite BP effects in young and adult Dahl-S rats. While it tended to increase BP in young salt hypertensive Dahl-S rats, it significantly lowered BP in the adult ones due to reduced sympathetic vasoconstriction. Importantly, high salt intake substantially reduced NO synthase activity in heart and kidney, and markedly increased superoxide production in kidneys and aorta of adult Dahl-S rats in which BP correlated positively with superoxide production in thoracic aorta and lipoperoxidation in kidneys. CONCLUSION: Chronic antioxidant therapy lowered BP only in adult salt hypertensive Dahl-S rats in which superoxide levels were increased in both kidneys and aorta. Blood pressure reduction induced by chronic tempol treatment is related to attenuated sympathetic vasoconstriction rather than to augmented NO-dependent vasodilatation.

• MeSH
• antioxidancia aplikace a dávkování   farmakologie   MeSH
• chlorid sodný škodlivé účinky   MeSH
• cyklické N-oxidy aplikace a dávkování   farmakologie   MeSH
• hypertenze farmakoterapie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• oxidační stres účinky léků   MeSH
• potkani inbrední Dahl MeSH
• spinové značení MeSH
• stárnutí MeSH
• sympatický nervový systém MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND AND AIMS: Nitric oxide (NO) is involved in the signalling and regulation of plant growth and development and responses to biotic and abiotic stresses. The photoperiod-sensitive mutant 7B-1 in tomato (Solanum lycopersicum) showing abscisic acid (ABA) overproduction and blue light (BL)-specific tolerance to osmotic stress represents a valuable model to study the interaction between light, hormones and stress signalling. The role of NO as a regulator of seed germination and ABA-dependent responses to osmotic stress was explored in wild-type and 7B-1 tomato under white light (WL) and BL. METHODS: Germination data were obtained from the incubation of seeds on germinating media of different composition. Histochemical analysis of NO production in germinating seeds was performed by fluorescence microscopy using a cell-permeable NO probe, and endogenous ABA was analysed by mass spectrometry. KEY RESULTS: The NO donor S-nitrosoglutathione stimulated seed germination, whereas the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) had an inhibitory effect. Under WL in both genotypes, PTIO strongly suppressed germination stimulated by fluridone, an ABA inhibitor. The stimulatory effect of the NO donor was also observed under osmotic stress for 7B-1 seeds under WL and BL. Seed germination inhibited by osmotic stress was restored by fluridone under WL, but less so under BL, in both genotypes. This effect of fluridone was further modulated by the NO donor and NO scavenger, but only to a minor extent. Fluorescence microscopy using the cell-permeable NO probe DAF-FM DA (4-amino-5-methylamino-2',7'-difluorofluorescein diacetate) revealed a higher level of NO in stressed 7B-1 compared with wild-type seeds. CONCLUSIONS: As well as defective BL signalling, the differential NO-dependent responses of the 7B-1 mutant are probably associated with its high endogenous ABA concentration and related impact on hormonal cross-talk in germinating seeds. These data confirm that light-controlled seed germination and stress responses include NO-dependent signalling.

• MeSH
• biologické modely MeSH
• cyklické N-oxidy farmakologie   MeSH
• donory oxidu dusnatého farmakologie   MeSH
• fluoresceiny analýza   MeSH
• fyziologický stres * účinky léků   účinky záření   MeSH
• imidazoly farmakologie   MeSH
• kinetika MeSH
• klíčení * účinky léků   účinky záření   MeSH
• kyselina abscisová metabolismus   MeSH
• mutace MeSH
• osmóza účinky léků   účinky záření   MeSH
• oxid dusnatý farmakologie   MeSH
• pyridony farmakologie   MeSH
• regulace genové exprese u rostlin účinky léků   účinky záření   MeSH
• regulátory růstu rostlin metabolismus   MeSH
• S-nitrosoglutathion farmakologie   MeSH
• scavengery volných radikálů farmakologie   MeSH
• semena rostlinná účinky léků   genetika   fyziologie   účinky záření   MeSH
• signální transdukce účinky léků   účinky záření   MeSH
• Solanum lycopersicum účinky léků   genetika   fyziologie   účinky záření   MeSH
• světlo * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Functional and morphological consequences of ischemic lesions are partially related to the production of reactive oxygen species (ROS). The aim of the study was to create a unilateral photothrombic lesion with minimal morphological changes and minor sensorimotor and cognitive deficits and also to test whether the application of ROS scavengers after the end of induction of ischemia had improved the functional outcome. Adult Wistar male rats were randomly divided into five groups: naive control, sham operated animals, animals with induced ischemia, and two groups of animals with induced ischemia and subsequent ROS scavenger application -melatonin or tempol. The group subjected to ischemia showed a significant decline in performance in sensorimotor tests and the Morris water maze (MWM) test, compared to control animals. Tempol (50 mg/kg, i.p.) did not improve sensorimotor function and did not change spatial learning. Melatonin (100 mg/kg, i.p.), on the contrary, resulted in a significant improvement in animals' performances. All the ischemia subjected animals had increased speed of swimming in the MWM test, compared to the control group. Our findings showed that subsequent application of ROS scavengers improve ischemia outcomes, with melatonin being more potent. Conversely, neither melatonin, nor tempol decreased swimming speed cased by ischemia.

• MeSH
• bludiště - učení MeSH
• časové faktory MeSH
• chování zvířat MeSH
• cyklické N-oxidy farmakologie   MeSH
• ischemie mozku patologie   MeSH
• ischemie patologie   MeSH
• kognice MeSH
• krysa rodu rattus MeSH
• melatonin farmakologie   MeSH
• neuroprotektivní látky farmakologie   MeSH
• potkani Wistar MeSH
• reaktivní formy kyslíku MeSH
• scavengery volných radikálů MeSH
• senzorická zpětná vazba MeSH
• spinové značení MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A deficiency in nitric oxide (NO) generation leads to salt-sensitive hypertension, but the role of increased superoxide (O(2)(-)) in such salt sensitivity has not been delineated. We examined the hypothesis that an enhancement in O(2)(-) activity induced by high-salt (HS) intake under deficient NO production contributes to the development of salt-sensitive hypertension. Endothelial NO synthase knockout (eNOS KO; total n = 64) and wild-type (WT; total n = 58) mice were given diets containing either normal (NS; 0.4%) or high-salt (HS; 4%) for 2 wk. During this period, mice were chronically treated with a O(2)(-) scavenger, tempol (400 mg/l), or an inhibitor of NADPH oxidase, apocynin (1 g/l), in drinking water or left untreated (n = 6-8 per group). Blood pressure was measured by radiotelemetry and 24-h urine samples were collected in metabolic cages. Basal mean arterial pressure (MAP) in eNOS KO was higher (125 +/- 4 vs. 106 +/- 3 mmHg) compared with WT. Feeding HS diet did not alter MAP in WT but increased it in eNOS KO to 166 +/- 9 mmHg. Both tempol and apocynin treatment significantly attenuated the MAP response to HS in eNOS KO (134 +/- 3 and 139 +/- 4 mmHg, respectively). Basal urinary 8-isoprostane excretion rates (U(Iso)V), a marker for endogenous O(2)(-) activity, were similar (2.8 +/- 0.2 and 2.4 +/- 0.3 ng/day) in both eNOS KO and WT mice. However, HS increased U(Iso)V more in eNOS KO than in WT (4.6 +/- 0.3 vs. 3.8 +/- 0.2 ng/day); these were significantly attenuated by both tempol and apocynin treatment. These data indicate that an enhancement in O(2)(-) activity contributes substantially to the development of salt-sensitive hypertension under NO-deficient conditions.

• MeSH
• acetofenony farmakologie   MeSH
• antioxidancia farmakologie   MeSH
• cyklické N-oxidy farmakologie   MeSH
• dinoprost analogy a deriváty   moč   MeSH
• hypertenze * etiologie   metabolismus   MeSH
• krevní tlak účinky léků   MeSH
• kuchyňská sůl farmakologie   škodlivé účinky   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• spinové značení MeSH
• superoxidy * metabolismus   MeSH
• synthasa oxidu dusnatého, typ III genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Results of our previous studies have suggested that enhanced generation of superoxide (O2(-)) may contribute to the pathophysiology of hypertension in Ren-2 transgenic rats (TGR). The present study was performed to evaluate in TGR the effects of chronic treatment with the O2(-) scavenger tempol and the antioxidant apocynin on the development of hypertension. Systolic blood pressure (SBP) was monitored from 30 to 99 days of age in TGR and in normotensive Hannover Sprague-Dawley (HanSD) rats. At the end of the experiment, urinary protein and 8-isoprostane excretion were determined and angiotensin II (ANG II) and malondialdehyde (MDA) levels were measured in kidney and cardiac tissues. Cardiac hypertrophy was assessed as the ratio of left heart ventricle weight to tibia length (LVW/TL). Although tempol and apocynin treatment in TGR significantly decreased 8-isoprostane excretion and MAD tissue concentrations as compared with untreated TGR, it did not alter the course of SBP, LVW/TL ratio, proteinuria or ANG II levels that were enhanced as compared with HanSD rats. Our data suggest that the development of hypertension in TGR is clearly ANG II-dependent but the contribution of oxidative stress to the development of hypertension in this model appears to be negligible.

• MeSH
• acetofenony farmakologie   MeSH
• analýza rozptylu MeSH
• angiotensin II analýza   fyziologie   krev   moč   MeSH
• antioxidancia farmakologie   MeSH
• časové faktory MeSH
• cyklické N-oxidy farmakologie   MeSH
• dinoprost analogy a deriváty   moč   MeSH
• hypertenze komplikace   patofyziologie   prevence a kontrola   MeSH
• kardiomegalie komplikace   prevence a kontrola   MeSH
• krevní tlak MeSH
• krysa rodu rattus MeSH
• ledviny chemie   MeSH
• malondialdehyd analýza   MeSH
• modely nemocí na zvířatech MeSH
• myokard chemie   MeSH
• náhodné rozdělení MeSH
• nemoci ledvin komplikace   prevence a kontrola   MeSH
• oxidační stres fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• proteinurie MeSH
• renin genetika   MeSH
• scavengery volných radikálů farmakologie   MeSH
• spinové značení MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH