Ellipticine is an antineoplastic agent, whose mode of antitumor and/or toxic side effects is based on DNA intercalation, inhibition of topoisomerase II and formation of DNA adducts mediated by cytochromes P450 and peroxidases. We investigated the formation and persistence of DNA adducts generated in rat, the animal model mimicking the bioactivation of ellipticine in human. Using (32)P-postlabeling, ellipticine-DNA adducts were found in liver, kidney, lung, spleen, heart and brain of female and male rats exposed to ellipticine (4, 40 and 80 mg/kg body weight, i.p.). The two major adducts were identical to the deoxyguanosine adducts generated in DNA by 13-hydroxy- and 12-hydroxyellipticine in vitro as confirmed by HPLC of the isolated adducts. At four post-treatment times (2 days, 2, 10 and 32 weeks) DNA adducts in rats treated with 80 mg/kg of ellipticine were analyzed in each tissue to study their long-term persistence. In all organs maximal adduct levels were found 2 days after administration. At all time points highest total adduct levels were in liver (402 adducts/10(8) nucleotides after 2 days and 3.6 adducts/10(8) nucleotides after 32 weeks), kidney and lung followed by spleen, heart and brain. Total adduct levels decreased over time to 0.8-8.3% of the initial levels till the latest time point and showed a biphasic profile, a rapid loss during the first 2 weeks was followed by a much slower decline till 32 weeks. These results, the first characterization of persistence of ellipticine-DNA adducts in vivo, are necessary to evaluate genotoxic side effects of ellipticine.

• MeSH
• adukty DNA * MeSH
• elipticiny toxicita   MeSH
• játra účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• ledviny účinky léků   metabolismus   MeSH
• mozek účinky léků   metabolismus   MeSH
• myokard metabolismus   MeSH
• plíce účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• protinádorové látky toxicita   MeSH
• slezina účinky léků   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA * MeSH
• elipticiny MeSH
• ellipticine MeSH Prohlížeč
• protinádorové látky MeSH

The study aimed to compare treatment retention for first-line TNF inhibitor (TNFi) in the ATTRA registry patients receiving either combination with conventional synthetic DMARDs or TNFi as monotherapy. A retrospective multicenter study analyzed data of all adult patients with rheumatoid arthritis (n = 3032) starting TNF inhibitor as the first-line biological therapy in combination with csDMARDs or in monotherapy from January 1st 2012 to December 31st 2020. Kaplan-Meier method was employed to calculate drug retentions. Survival curves of treatment retentions were compared through Log-rank test between the studied subgroups. The hazard ratio for drug discontinuation was assessed through univariate cox regression models. In patients who started the first line TNFi therapy, the median treatment retention was 47.7 (42.2; 53.1) months for combination therapy and 22.7 (14.9; 30.6) months for TNFi monotherapy (p < 0.001). Estimated one-year survival was higher in patients on TNFi combined with csDMARDs as compared with TNFi monotherapy (75.3% vs 65.7%); two-year survival rate was 63.2% vs 49.2%, three-year survival rate was 55.4% vs 42.4% and five-year survival 44.9% vs 26.4% of patients. The estimated survival on the first TNFi was higher in patients taking combination therapy with methotrexate than with other csDMARDs (p = 0.003). Use of csDMARDs co-medication was associated with significantly better first TNFi drug survival compared to monotherapy. The combination of TNFi with MTX is more effective than the combination with leflunomide, which did not demonstrate a significant effect.

• Klíčová slova
• Drug persistence, Methotrexate, Registry, Rheumatoid arthritis, TNF inhibitor, csDMARDs,
• MeSH
• antirevmatika * škodlivé účinky   MeSH
• dospělí MeSH
• inhibitory TNF terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• methotrexát škodlivé účinky   MeSH
• registrace MeSH
• retrospektivní studie MeSH
• revmatoidní artritida * chemicky indukované   diagnóza   farmakoterapie   MeSH
• TNF-alfa terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• antirevmatika * MeSH
• inhibitory TNF MeSH
• methotrexát MeSH
• TNF-alfa MeSH

OBJECTIVE: Psychiatric disorders are associated with an increased risk of cardiovascular diseases and may result in additional risk of non-adherence. No data on the influence of concomitant psychiatric drug use on patients' beliefs and persistence related to cardiovascular medication are available. The objective of this study was to assess to what extent the use of concomitant psychiatric drugs is associated with patients' beliefs about and persistence with chronic cardiovascular medication. METHODS: An observational study in patients using cardiovascular medication was conducted. A mailed questionnaire containing socio-demographical questions and a measure of beliefs about medication (Beliefs about Medicines Questionnaire - specific) was sent to patients selected from fifteen participating pharmacies. Persistence was evaluated based on pharmacy records. RESULTS: Of the 1547 included patients, 551 responded to key questions in the questionnaire and were included for beliefs about medication analysis. In concomitant users of psychiatric drugs significantly higher necessity (17.0 vs. 16.0) and higher concerns (14.3 vs. 13.3), as well as higher proportion of ambivalent (34.5% vs. 25.6%) and lower proportion of indifferent patients (24.1% vs. 33.0%) were found compared with non-users (p < 0.05). 65.2% (n = 1009) of patients were persistent on all their cardiovascular drugs. There was no significant association between concomitant use of psychiatric drugs and non-persistence (OR = 1.2; 95% CI 0.9-1.5). CONCLUSION: Concomitant use of psychiatric drugs was found to be associated with increased beliefs about the necessity of and concerns about cardiovascular medication. Clinicians caring for cardiovascular patients should give additional attention to identifying patients' beliefs about medication among those concomitantly using psychiatric drugs.

• MeSH
• antipsychotika terapeutické užití   MeSH
• dospělí MeSH
• hodnocení adherence k farmakoterapii * MeSH
• kardiovaskulární látky terapeutické užití   MeSH
• kardiovaskulární nemoci komplikace   farmakoterapie   MeSH
• kombinovaná farmakoterapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• průřezové studie MeSH
• průzkumy a dotazníky MeSH
• psychotické poruchy komplikace   farmakoterapie   MeSH
• senioři MeSH
• zdraví - znalosti, postoje, praxe * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antipsychotika MeSH
• kardiovaskulární látky MeSH

OBJECTIVE: We aimed to analyse the effect of the introduction of fingolimod, the first oral disease-modifying therapy, on treatment utilisation and persistence in an international cohort of patients with multiple sclerosis (MS). METHODS: MSBASIS, a prospective, observational sub-study of the MSBase registry, collects demographic, clinical and paraclinical data on patients followed from MS onset (n=4718). We conducted a multivariable conditional risk set survival analysis to identify predictors of treatment discontinuation, and to assess if the introduction of fingolimod has altered treatment persistence. RESULTS: A total of 2640 patients commenced immunomodulatory therapy. Following the introduction of fingolimod, patients were more likely to discontinue all other treatments (hazard ratio 1.64, p<0.001) while more patients switched to fingolimod than any other therapy (42.3% of switches). Patients switched to fingolimod due to convenience. Patients treated with fingolimod were less likely to discontinue treatment compared with other therapies (p<0.001). Female sex, country of residence, younger age, a high Expanded Disability Status Scale score and relapse activity were all independently associated with higher rates of treatment discontinuation. CONCLUSION: Following the availability of fingolimod, patients were more likely to discontinue injectable treatments. Those who switched to fingolimod were more likely to do so for convenience. Persistence was improved on fingolimod compared to other medications.

• Klíčová slova
• MSBase, Multiple sclerosis, disease-modifying therapy, fingolimod, medication persistence,
• MeSH
• adherence k farmakoterapii * MeSH
• aplikace orální MeSH
• časové faktory MeSH
• demyelinizační nemoci diagnóza   farmakoterapie   imunologie   MeSH
• dospělí MeSH
• fingolimod hydrochlorid aplikace a dávkování   škodlivé účinky   MeSH
• imunosupresiva aplikace a dávkování   škodlivé účinky   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• multivariační analýza MeSH
• náhrada léků * MeSH
• proporcionální rizikové modely MeSH
• prospektivní studie MeSH
• registrace MeSH
• relabující-remitující roztroušená skleróza diagnóza   farmakoterapie   imunologie   MeSH
• rizikové faktory MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fingolimod hydrochlorid MeSH
• imunosupresiva MeSH

BACKGROUND: An integrated analysis of phase III trials in patients with advanced solid tumors demonstrated superiority of denosumab over zoledronic acid in preventing skeletal-related events. A drug's clinical efficacy, however, depends on regular and continued administration (persistence); persistence in Slovak real-life is yet undetermined for denosumab in the oncology indication. PATIENTS AND METHODS: This was a single-arm, prospective, observational, non-interventional study in patients with bone metastases from solid tumors treated with denosumab every 4 weeks in real-world clinical practice in 5 European countries. The results of the 54 patients from Slovakia are presented here. Persistence was defined as denosumab administration at ≤ 35-day intervals over 24 or 48 weeks, respectively. RESULTS: Previous skeletal-related events were found in 5.6% of patients. 84.8% were persistent over 24 weeks and 61.4 % over 48 weeks. The median (95% confidence interval (CI)) time to non-persistence was 306.5 days (Q1 = 151.0; Q3 = 315.0). The most frequent reason for non-persistence was delayed administration of denosumab. There was a trend towards weaker analgesics over time, with > 70% of patients not requiring any analgesics. Serum calcium remained within the normal range throughout the whole study. Adjudicated osteonecrosis of the jaw was not documented in any Slovak patient. CONCLUSION: Most patients received denosumab regularly once every 4 weeks over 24 weeks of treatment. Non-persistence was mainly due to delayed administration. The incidence of adverse drug reactions was in line with expectations from previous studies, osteonecrosis of the jaw did not occur in any of the patients involved in the study.

• Klíčová slova
• bone metastases, denosumab, observational study, persistence, solid tumors,
• MeSH
• denosumab MeSH
• lidé MeSH
• nádory kostí * MeSH
• osteonekróza * MeSH
• prospektivní studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• pozorovací studie MeSH
• Geografické názvy
• Slovenská republika MeSH
• Názvy látek
• denosumab MeSH

• Klíčová slova
• ALLERGY/experimental *, STREPTOCOCCAL INFECTIONS/experimental *,
• MeSH
• alergie * MeSH
• aplikace intranazální * MeSH
• králíci MeSH
• Streptococcus * MeSH
• streptokokové infekce * MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Bacterial persistence in clinical microbiology is a phenomenon where the bacterial subpopulation of any bacterial strain, without having been exposed to an antibiotic, is already persistent to it. In clinical bacterial strains, persistence is not tested at all and the role of this phenomenon in the treatment of bacterial infections has not yet been evaluated. Therefore, the aim of the article is to highlight the significance of this probably global phenomenon in the treatment of bacterial infections with antibiotics. Also described are the mechanisms of its origin and some manner that could potentially reduce the frequency of these antibiotic-resistant bacterial cells in the bacterial population.

• MeSH
• antibakteriální látky * farmakologie   MeSH
• Bacteria * účinky léků   MeSH
• bakteriální infekce * mikrobiologie   MeSH
• bakteriální léková rezistence * MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antibakteriální látky * MeSH

PURPOSE: In the integrated analysis of phase III head-to-head trials in patients with advanced solid tumors, denosumab demonstrated superiority over zoledronic acid in preventing skeletal-related events (SREs). Regular and continued drug use (persistence) is a precondition of clinical efficacy; persistence in real-life is yet undetermined for denosumab. METHODS: This was a single-arm, prospective, observational, non-interventional study in 598 patients with bone metastases from breast, prostate, lung, or other solid tumors treated with denosumab every four weeks in real-world clinical practice in Austria, Czech Republic, Hungary, Slovakia, and Bulgaria. Persistence was defined as denosumab administration at ≤ 35-day intervals over 24 or 48 weeks, respectively. RESULTS: Previous SREs were found in 10.9% of patients. 62.6% were persistent over 24 weeks and 40.1% over 48 weeks. The Kaplan-Meier median (95% CI) time to non-persistence was 274.0 days (232.0, 316.0). The most frequent reason for non-persistence was delayed administration. There was a trend towards weaker analgesics over time, with approximately 60% of patients not requiring any analgesics. Serum calcium remained within the normal range throughout the study. Adjudicated osteonecrosis of the jaw was documented in three patients with an incidence per patient-year (95% CI) of 0.012 (0.004, 0.029). CONCLUSIONS: Most patients received denosumab regularly once every four weeks over 24 weeks of treatment. Non-persistence was mainly due to delayed administration. The incidence of adverse drug reactions, especially of osteonecrosis of the jaw, was in line with expectations from previous studies.

• Klíčová slova
• Bone metastases, Denosumab, Observational study, Persistence, Solid tumors,
• MeSH
• denosumab aplikace a dávkování   škodlivé účinky   MeSH
• dospělí MeSH
• inhibitory kostní resorpce aplikace a dávkování   škodlivé účinky   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádory kostí farmakoterapie   sekundární   MeSH
• nádory farmakoterapie   patologie   MeSH
• osteonekróza chemicky indukované   MeSH
• prospektivní studie MeSH
• rozvrh dávkování léků MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• Názvy látek
• denosumab MeSH
• inhibitory kostní resorpce MeSH

BACKGROUND AND OBJECTIVE: Non-persistence with secondary preventive measures, including medications such as statins, adversely affects the prospects of successful outcomes. This study was aimed at evaluating non-persistence with statin therapy in cohorts of young and elderly patients after a transient ischaemic attack (TIA) and identifying patient-associated characteristics that influence the risk for non-persistence. METHODS: The study cohorts included 797 adult patients who were initiated on statin therapy following a TIA diagnosis between 1 January 2010 and 31 December 2010. Patients were followed up for 3 years and those with a treatment gap of at least a 6-month period were considered 'non-persistent'. In order to identify any age-related differences, all analyses were conducted in the entire study cohort (n = 797) as well as separately in the 'younger' (aged <65 years, n = 267) and the 'older' (aged ≥65 years, n = 530) patients. RESULTS: Non-persistence was significantly more common in younger patients compared to older patients (67.8% vs. 49.1%; p < 0.001). Factors that decreased the probability of non-persistence in younger and older patients included diabetes mellitus (hazard ratio [HR] = 0.72 and HR = 0.64, respectively) and hypercholesterolaemia (HR = 0.43 and HR = 0.62, respectively). Female gender (HR = 1.42) was associated with a higher and increasing number of medications taken (HR = 0.93), with lower probability for non-persistence in younger patients but not in the older patients. CONCLUSIONS: Our results indicate that certain patients with TIA require special counselling to improve persistence with statin therapy. These include younger patients, especially females and those not on polypharmacy, and both younger and older patients without diabetes mellitus or hypercholesterolaemia.

• MeSH
• adherence k farmakoterapii * MeSH
• diabetes mellitus epidemiologie   MeSH
• hypercholesterolemie farmakoterapie   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• polypharmacy MeSH
• proporcionální rizikové modely MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• statiny terapeutické užití   MeSH
• tranzitorní ischemická ataka farmakoterapie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• statiny MeSH

Persistence of drug-resistant quiescent leukemic stem cells (LSC) and impaired natural killer (NK) cell immune response account for relapse of chronic myelogenous leukemia (CML). Inactivation of protein phosphatase 2A (PP2A) is essential for CML-quiescent LSC survival and NK cell antitumor activity. Here we show that MIR300 has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively. MIR300 is upregulated in CML LSCs and NK cells by bone marrow microenvironment (BMM) signals to induce quiescence and impair immune response, respectively. Conversely, BCR-ABL1 downregulates MIR300 in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating TUG1 long noncoding RNA that uncouples and limits MIR300 function to cytostasis. Genetic and pharmacologic MIR300 modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis in vitro and in patient-derived xenografts; hence, the importance of MIR300 and PP2A activity for CML development and therapy.

• MeSH
• buňky NK MeSH
• chronická myeloidní leukemie * farmakoterapie   MeSH
• inhibitory proteinkinas metabolismus   MeSH
• lidé MeSH
• mikro RNA * genetika   MeSH
• nádorové kmenové buňky MeSH
• nádorové mikroprostředí genetika   MeSH
• proteinfosfatasa 2 genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• mikro RNA * MeSH
• MIRN300 microRNA, human MeSH Prohlížeč
• proteinfosfatasa 2 MeSH