Cardiovascular disease is the main cause of death worldwide, making it crucial to search for new therapies to mitigate major adverse cardiac events (MACEs) after a cardiac ischemic episode. Drugs in the class of the glucagon-like peptide-1 receptor agonists (GLP1Ra) have demonstrated benefits for heart function and reduced the incidence of MACE in patients with diabetes. Previously, we demonstrated that a short-acting GLP1Ra known as DMB (2-quinoxalinamine, 6,7-dichloro-N-[1,1-dimethylethyl]-3-[methylsulfonyl]-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline or compound 2, Sigma) also mitigates adverse postinfarction left ventricular remodeling and cardiac dysfunction in lean mice through activation of parkin-mediated mitophagy following infarction. Here, we combined proteomics with in silico analysis to characterize the range of effects of DMB in vivo throughout the course of early postinfarction remodeling. We demonstrate that the mitochondrion is a key target of DMB and mitochondrial respiration, oxidative phosphorylation and metabolic processes such as glycolysis and fatty acid beta-oxidation are the main biological processes being regulated by this compound in the heart. Moreover, the overexpression of proteins with hub properties identified by protein-protein interaction networks, such as Atp2a2, may also be important to the mechanism of action of DMB. Data are available via ProteomeXchange with identifier PXD027867.

• Klíčová slova
• DMB, cellular respiration, early cardiac remodeling, glucagon-like peptide-1 receptor agonists, metabolism, mitochondrion, proteomics,
• MeSH
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• chinoxaliny aplikace a dávkování   farmakologie   MeSH
• glykolýza MeSH
• mapy interakcí proteinů MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• oxidativní fosforylace MeSH
• proteomika metody   MeSH
• remodelace komor účinky léků   MeSH
• sarkoplazmatická Ca2+-ATPáza metabolismus   MeSH
• srdeční komory metabolismus   MeSH
• srdeční mitochondrie metabolismus   MeSH
• výpočetní biologie MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• Atp2a2 protein, mouse MeSH Prohlížeč
• chinoxaliny MeSH
• sarkoplazmatická Ca2+-ATPáza MeSH

BACKGROUND & AIMS: Eight-week glecaprevir/pibrentasvir leads to high rates of sustained virological response at post-treatment week 12 (SVR12) across HCV genotypes (GT) 1-6 in treatment-naïve patients without cirrhosis. We evaluated glecaprevir/pibrentasvir once daily for 8 weeks in treatment-naïve patients with compensated cirrhosis. METHODS: EXPEDITION-8 was a single-arm, multicenter, phase IIIb trial. The primary and key secondary efficacy analyses were to compare the lower bound of the 95% CI of the SVR12 rate in i) patients with GT1,2,4-6 in the per protocol (PP) population, ii) patients with GT1,2,4-6 in the intention-to-treat (ITT) population, iii) patients with GT1-6 in the PP population, and iv) patients with GT1-6 in the ITT population, to pre-defined efficacy thresholds based on historical SVR12 rates for 12 weeks of glecaprevir/pibrentasvir in the same populations. Safety was also assessed. RESULTS: A total of 343 patients were enrolled. Most patients were male (63%), white (83%), and had GT1 (67%). The SVR12 rate in patients with GT1-6 was 99.7% (n/N = 334/335; 95%CI 98.3-99.9) in the PP population and 97.7% (n/N = 335/343; 95% CI 96.1-99.3) in the ITT population. All primary and key secondary efficacy analyses were achieved. One patient (GT3a) experienced relapse (0.3%) at post-treatment week 4. Common adverse events (≥5%) were fatigue (9%), pruritus (8%), headache (8%), and nausea (6%). Serious adverse events (none related) occurred in 2% of patients. No adverse event led to study drug discontinuation. Clinically significant laboratory abnormalities were infrequent. CONCLUSIONS: Eight-week glecaprevir/pibrentasvir was well tolerated and led to a similarly high SVR12 rate as the 12-week regimen in treatment-naïve patients with chronic HCV GT1-6 infection and compensated cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03089944. LAY SUMMARY: This study was the first to evaluate an 8-week direct-acting antiviral (DAA) regimen active against all major types of hepatitis C virus (HCV) in untreated patients with compensated cirrhosis. High virological cure rates were achieved with glecaprevir/pibrentasvir across HCV genotypes 1-6, and these high cure rates did not depend on any patient or viral characteristics present before treatment. This may simplify care and allow non-specialist healthcare professionals to treat these patients, contributing to global efforts to eliminate HCV.

• Klíčová slova
• Chronic HCV infection, Compensated cirrhosis, Direct-acting antiviral, Glecaprevir/pibrentasvir, HCV elimination, Hepatitis C virus, Pangenotypic, Short duration,
• MeSH
• antivirové látky aplikace a dávkování   škodlivé účinky   MeSH
• benzimidazoly aplikace a dávkování   škodlivé účinky   MeSH
• chinoxaliny aplikace a dávkování   škodlivé účinky   MeSH
• chronická hepatitida C krev   komplikace   farmakoterapie   virologie   MeSH
• cyklopropany aplikace a dávkování   škodlivé účinky   MeSH
• fixní kombinace léků MeSH
• genotyp * MeSH
• Hepacivirus enzymologie   genetika   MeSH
• jaterní cirhóza komplikace   farmakoterapie   MeSH
• kyseliny aminoisomáselné aplikace a dávkování   škodlivé účinky   MeSH
• leucin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• lidé středního věku MeSH
• lidé MeSH
• makrocyklické laktamy aplikace a dávkování   škodlivé účinky   MeSH
• polymorfismus genetický MeSH
• prolin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• pyrrolidiny aplikace a dávkování   škodlivé účinky   MeSH
• RNA virová krev   genetika   MeSH
• senioři MeSH
• setrvalá virologická odpověď MeSH
• sulfonamidy aplikace a dávkování   škodlivé účinky   MeSH
• virové nestrukturální proteiny genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• benzimidazoly MeSH
• chinoxaliny MeSH
• cyklopropany MeSH
• fixní kombinace léků MeSH
• glecaprevir MeSH Prohlížeč
• kyseliny aminoisomáselné MeSH
• leucin MeSH
• makrocyklické laktamy MeSH
• NS-5 protein, hepatitis C virus MeSH Prohlížeč
• NS3 protein, hepatitis C virus MeSH Prohlížeč
• pibrentasvir MeSH Prohlížeč
• prolin MeSH
• pyrrolidiny MeSH
• RNA virová MeSH
• sulfonamidy MeSH
• virové nestrukturální proteiny MeSH

Mequindox (MEQ) is a synthetic antimicrobial agent of quinoxaline-1,4-dioxide group (QdNOs). The liver is regarded as the toxicity target of QdNOs, and the role of N → O group-associated various toxicities mediated by QdNOs is well recognized. However, the mechanism underlying the in vivo effects of MEQ on the liver, and whether the metabolic pathway of MEQ is altered in response to the pathophysiological conditions still remain unclear. We now provide evidence that MEQ triggers oxidative damage in the liver. Moreover, using LC/MS-ITTOF analysis, two metabolites of MEQ were detected in the liver, which directly confirms the potential connection between N → O group reduction metabolism of MEQ and liver toxicity. The gender difference in MEQ-induced oxidative stress might be due to adrenal toxicity and the generation of M4 (2-isoethanol 1-desoxymequindox). Furthermore, up-regulation of the MAPK and Nrf2-Keap1 family and phase II detoxifying enzymes (HO-1, GCLC and NQO1) were also observed. The present study demonstrated for the first time the protein peroxidation and a proposal metabolic pathway after chronic exposure of MEQ, and illustrated that the MAPK, Nrf2-Keap1 and NF-кB signaling pathways, as well as the altered metabolism of MEQ, were involved in oxidative toxicity mediated by MEQ in vivo.

• MeSH
• antiinfekční látky aplikace a dávkování   farmakokinetika   toxicita   MeSH
• chinoxaliny aplikace a dávkování   farmakokinetika   toxicita   MeSH
• faktor 2 související s NF-E2 metabolismus   MeSH
• játra účinky léků   metabolismus   MeSH
• KEAP-1 metabolismus   MeSH
• MAP kinasový signální systém * MeSH
• myši MeSH
• oxidace-redukce MeSH
• oxidační stres * MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiinfekční látky MeSH
• chinoxaliny MeSH
• faktor 2 související s NF-E2 MeSH
• KEAP-1 MeSH
• Keap1 protein, mouse MeSH Prohlížeč
• Mequindox MeSH Prohlížeč
• Nfe2l2 protein, mouse MeSH Prohlížeč

Excretion, disposition, and metabolism of [(3)H]-quinocetone in rats, pigs, broilers, and carp following oral administration were investigated. After a single p.o. dose, total radioactivity was rapidly excreted, with ⩾94% in all species within 14 days. Fecal excretion of radioactivity was 68% and 65% of the administered dose in rats and pigs, respectively, with the remainder excreted in the urine. Six hours after the last of seven daily oral administrations of (3)H-labeled QCT, radioactivity was found to be distributed throughout all tissues, with the majority of radioactivity cleared within 7 days, and elimination was the slowest from the liver and kidney. QCT was extensively metabolized in all of the species, and the primary changes included N-O group reduction, carbonyl group reduction, double bond reduction, and hydroxylation. The major tissue metabolites of QCT were Q2, Q4, Q5, Q8, and Q9 in rats; Q1, Q2, Q3, Q4, and Q5 in pigs; Q1, Q2, Q3, Q4, and Q7 in broilers; and Q1, Q2 in carp. This confirmed the potential link between QCT metabolism through N-O group reduction and its organ toxicity. The results of the present study provide important data that could help understand the relationship between the toxicities and metabolic disposition of QCT.

• Klíčová slova
• Disposition, Excretion, Metabolism, Quinocetone, Radioactivity isotope tracing, Toxicology,
• MeSH
• aplikace orální MeSH
• chinoxaliny aplikace a dávkování   metabolismus   farmakokinetika   toxicita   MeSH
• feces MeSH
• kapři MeSH
• kur domácí MeSH
• potkani Wistar MeSH
• Sus scrofa MeSH
• tkáňová distribuce MeSH
• tritium farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chinoxaliny MeSH
• quinocetone MeSH Prohlížeč
• tritium MeSH

This paper deals with an analytical method based on two dimensional capillary electrophoresis (CITP-CZE coupling) with simple UV-detection for the determination of a highly effective drug - varenicline. The method was elaborated with the possibility of its future connection with an advanced detection ending - mass spectrometry. The electrolytes for the CITP (LE = 10 mM NH4Ac + 5 mM HAc + 0,05% m-HEC; TE = 10 mM HAc) and CZE (BGE = 20 mM HAc) separation of varenicline were selected considering such requirements. The UV detector was set at the constant wavelength of 237 nm. The presented CITP-CZE-UV combination enabled rapid and effective evaluation of varenicline in the dosage forms with LOD 5.92 ng/ml.

• MeSH
• benzazepiny aplikace a dávkování   analýza   MeSH
• chinoxaliny aplikace a dávkování   analýza   MeSH
• elektroforéza kapilární metody   MeSH
• elektrolyty chemie   MeSH
• vareniklin MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzazepiny MeSH
• chinoxaliny MeSH
• elektrolyty MeSH
• vareniklin MeSH

BACKGROUND AND AIMS: Cross-study comparisons of effect sizes suggest that varenicline is more effective than nicotine replacement therapy (NRT) in aiding smoking cessation, but evidence from direct comparisons is limited. This study compared biochemically verified 52-week sustained abstinence rates in smokers attending the same clinical service according to whether they used varenicline or NRT in their quit attempt. METHODS: This was a prospective cohort study of 855 smokers attending a large smoking cessation clinic who used their choice of NRT product or varenicline in their quit attempt. All received the same behavioural support programme and chose their medication option (n = 519 varenicline; n = 336 NRT). The primary outcome measure was self-report of 52 weeks' abstinence following the target quit date confirmed by expired air carbon monoxide concentration. Baseline measures included socio-demographic variables, mental health diagnoses, measures of smoking, cigarette dependence and past use of NRT or varenicline. RESULTS: The 52-week abstinence rates were 42.8% versus 31.0% in those using varenicline versus NRT, respectively (P < 0.001). After adjusting for all baseline variables, the odds of remaining abstinent for 52 weeks were 2.03 (95% CI 1.46-2.82), P < 0.001 times higher in those using varenicline than those using NRT. CONCLUSIONS: Smokers in the same behavioural support programme who use varenicline appear to have a greater probability of achieving long-term abstinence than those using their choice of nicotine replacement therapy options, even after adjusting for potentially confounding smoker characteristics.

• Klíčová slova
• NRT, smoking cessation, varenicline,
• MeSH
• benzazepiny aplikace a dávkování   MeSH
• chinoxaliny aplikace a dávkování   MeSH
• dechové testy MeSH
• lidé středního věku MeSH
• lidé MeSH
• nikotinoví agonisté aplikace a dávkování   MeSH
• odvykání kouření metody   MeSH
• oxid uhelnatý analýza   MeSH
• prevence kouření MeSH
• prospektivní studie MeSH
• prostředky pro ukončení závislosti na tabáku statistika a číselné údaje   MeSH
• vareniklin MeSH
• výsledek terapie MeSH
• způsoby aplikace léků MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• benzazepiny MeSH
• chinoxaliny MeSH
• nikotinoví agonisté MeSH
• oxid uhelnatý MeSH
• vareniklin MeSH

Excitatory amino acids play an important role in generation of epileptic seizures. To study the participation of different types of their receptors in cortical epileptic afterdischarges, a noncompetitive NMDA receptor antagonist dizocilpine and a competitive AMPA receptor antagonist NBQX were used. Adult rats with implanted epidural stimulation and registration electrodes were pretreated either with NBQX (30 or 60 mg/kg i.p.) or with dizocilpine (0.1 or 0.5 mg/kg i.p.) and low-frequency stimulation of sensorimotor cortical area was repeatedly applied with stepwise increased current intensities. Lower dose of NBQX unexpectedly decreased thresholds for elicitation of spike-and-wave afterdischarges (ADs), clonic seizures accompanying this type of ADs and for transition into the second, limbic type of ADs. Lower dose of dizocilpine increased these three thresholds. Higher doses of either drug did not significantly change threshold intensities. Duration of ADs was also influenced by the two antagonists in opposite directions: higher dose of NBQX resulted in prolongation of ADs mainly due to an increased duration of the spike-and-wave part of ADs whereas dizocilpine shortened ADs in a dose-dependent manner affecting both types of ADs. In addition, NBQX did not influence interhemispheric responses meanwhile dizocilpine moderately suppressed these evoked potentials. According to our results, NMDA receptors are important for generation of cortical epileptic afterdischarges meanwhile the role of AMPA receptors is not clear and has to be analyzed.

• MeSH
• antagonisté excitačních aminokyselin MeSH
• chinoxaliny aplikace a dávkování   MeSH
• dizocilpinmaleát aplikace a dávkování   MeSH
• elektrická stimulace škodlivé účinky   MeSH
• elektroencefalografie metody   MeSH
• epilepsie etiologie   patologie   patofyziologie   prevence a kontrola   MeSH
• evokované potenciály účinky léků   fyziologie   účinky záření   MeSH
• krysa rodu Rattus MeSH
• mozková kůra účinky léků   MeSH
• potkani Wistar MeSH
• vztah dávky záření a odpovědi MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline MeSH Prohlížeč
• antagonisté excitačních aminokyselin MeSH
• chinoxaliny MeSH
• dizocilpinmaleát MeSH

In three experiments, 101 early-weaned piglets were given for 21 days feed mixtures containing 200 to 284 g crude protein per kg, the ratio of digestible energy to protein being 56 to 83. The effect of an up to 4% supplement of lard or cyadox as growth stimulant was studied as exerted on protein economy. In comparison with the system in which the animals were given the COS 1 high-protein complete mixture in the first week followed by the administration of COS 2, enrichment of the COS 2 mixture with cyadox increased the intake of feed and the growth of the piglets; on the other hand, it reduced the consumption of feed and crude protein per kg of gain, particularly in the first week (by 19, 33, 10 and 33%, respectively). The content of 25 g of lard in kg of the COS 2 mixture increased the efficiency of its administration to a higher degree than the addition of 50 mg of cyadox, mainly in the first post-weaning week. The increase in the energy value of feed through fortification with lard had a more pronounced influence on the effectiveness of the mixture with cyadox supplement as compared with the increase in the energy value of the feed mixture resulting from the addition of maize. It was only in individual cases that lard administration increased the concentration of cholesterol and non-esterified fatty acids in blood plasma, or such an increase was only insignificant. The use of a feed mixture containing 200 to 214 g crude protein per kg and a lard or growth stimulant supplement can increase the efficiency of the nutrition of piglets weaned at the age of four weeks; in this way it is possible, with economic advantage, to replace the COS 1 mixture inducing undesired hyper-uremia. Cyadox in mixture A 1, administered in the fourth and fifth week after the weaning of the piglets, increased weight gains by 14% and reduced feed consumption by 10% without reducing growth rate.

• MeSH
• chinoxaliny aplikace a dávkování   MeSH
• dietní tuky aplikace a dávkování   MeSH
• krmivo pro zvířata * MeSH
• odstavení * MeSH
• prasata růst a vývoj   MeSH
• růstové látky aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• chinoxaliny MeSH
• cyadox MeSH Prohlížeč
• dietní tuky MeSH
• růstové látky MeSH

Two feed mixtures were produced, each containing the antimicrobial preparation Carbadox and different amounts of furazolidone. Their fortnightly administration in starters to piglets weaned at the age of 25--31 days prevented mortality and stimulated somatic growth and feed utilization. Premix with a higher content of furazolidone markedly depressed the clinical symptoms of gastro-enteritis and reduced the number of the haemolytic germs of E. coli in the contents of the duodenum and jejunum. The presence of furazolidone in the feed completely eliminated enteral disorders and delayed the onset of the disease, or alleviated its course, in cases of severe diarrhoea, which killed, in the control group, the piglets of the same litter. Weight gains were significantly increased, particularly in the first post-weaning week, the difference from the control being up to 520%. Almost 0.5 kg of the COS 2 starter was saved per 1 kg of piglet live weight gain. Under the current farming conditions of five agricultural enterprises the weight gains during the ten days of the administration of the medicated feed were increased, on an average by 0.84-1.32 kg. In herds where the untreated piglets put on less than 1 kg the gains were increased by 96--124%. It is recommended to administer the new-developed medicated premix to prevent losses due to alteration of the intestinal microflora in early-weaned piglets.

• MeSH
• chinoxaliny aplikace a dávkování   MeSH
• furazolidon aplikace a dávkování   MeSH
• karbadox aplikace a dávkování   MeSH
• krmivo pro zvířata MeSH
• nemoci prasat prevence a kontrola   MeSH
• nemoci střev veterinární   MeSH
• odstavení MeSH
• poruchy růstu veterinární   MeSH
• prasata MeSH
• průjem prevence a kontrola   veterinární   MeSH
• vitamin E aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• chinoxaliny MeSH
• furazolidon MeSH
• karbadox MeSH
• vitamin E MeSH