BACKGROUND: Adherence to rhinitis treatment has been insufficiently assessed. We aimed to use data from the MASK-air mHealth app to assess adherence to oral antihistamines (OAH), intra-nasal corticosteroids (INCS) or azelastine-fluticasone in patients with allergic rhinitis. METHODS: We included regular European MASK-air users with self-reported allergic rhinitis and reporting at least 1 day of OAH, INCS or azelastine-fluticasone. We assessed weeks during which patients answered the MASK-air questionnaire on all days. We restricted our analyses to data provided between January and June, to encompass the pollen seasons across the different assessed countries. We analysed symptoms using visual analogue scales (VASs) and the combined symptom-medication score (CSMS), performing stratified analyses by weekly adherence levels. Medication adherence was computed as the proportion of days in which patients reported rhinitis medication use. Sensitivity analyses were performed considering all weeks with at most 1 day of missing data and all months with at most 4 days of missing data. RESULTS: We assessed 8212 complete weeks (1361 users). Adherence (use of medication > 80% days) to specific drug classes ranged from 31.7% weeks for azelastine-fluticasone to 38.5% weeks for OAH. Similar adherence to rhinitis medication was found in users with or without self-reported asthma, except for INCS (better adherence in asthma patients). VAS and CSMS levels increased from no adherence to full adherence, except for INCS. A higher proportion of days with uncontrolled symptoms was observed in weeks with higher adherence. In full adherence weeks, 41.2% days reported rhinitis co-medication. The sensitivity analyses displayed similar results. CONCLUSIONS: A high adherence was found in patients reporting regular use of MASK-air. Different adherence patterns were found for INCS compared to OAH or azelastine-fluticasone that are likely to impact guidelines.
- MeSH
- adherence k farmakoterapii * MeSH
- antialergika terapeutické užití MeSH
- antihistaminika terapeutické užití MeSH
- dospělí MeSH
- flutikason terapeutické užití aplikace a dávkování MeSH
- ftalaziny terapeutické užití MeSH
- hormony kůry nadledvin terapeutické užití aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- průzkumy a dotazníky MeSH
- pyl imunologie MeSH
- roční období * MeSH
- sezónní alergická rýma * farmakoterapie epidemiologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
Hepatocellular carcinoma (HCC) cells critically depend on PARP1 and CHK1 activation for survival. Combining the PARP inhibitor (PARPi) olaparib with a CHK1 inhibitor (MK-8776, CHK1i) produced a synergistic effect, reducing cell viability and inducing marked oxidative stress and DNA damage, particularly in the HepG2 cells. This dual treatment significantly increased apoptosis markers, including γH2AX and caspase-3/7 activity. Both HCC cell lines exhibited heightened sensitivity to the combined treatment. The effect of drugs on the expression of proliferation markers in an olaparib-resistant patient-derived xenograft (PDX) model of ovarian cancer was also investigated. Ovarian tumors displayed reduced tissue growth, as reflected by a drop in proliferation marker Ki-67 levels in response to PARPi combined with CHK1i. No changes were observed in corresponding liver tissues using Ki-67 and pCHK staining, which indicates the absence of metastases and a hepatotoxic effect. Thus, our results indicate that the dual inhibition of PARP and CHK1 may prove to be a promising therapeutic approach in the treatment of primary HCC as well as OC tumors without the risk of liver metastases, especially in patients with olaparib-resistant tumor profiles.
- MeSH
- apoptóza účinky léků MeSH
- buňky Hep G2 MeSH
- checkpoint kinasa 1 metabolismus antagonisté a inhibitory MeSH
- ftalaziny * farmakologie MeSH
- hepatocelulární karcinom * farmakoterapie patologie metabolismus MeSH
- játra účinky léků patologie metabolismus MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory jater * farmakoterapie patologie metabolismus MeSH
- nádory vaječníků * farmakoterapie patologie metabolismus MeSH
- PARP inhibitory farmakologie terapeutické užití MeSH
- piperaziny * farmakologie MeSH
- poškození DNA účinky léků MeSH
- proliferace buněk účinky léků MeSH
- protokoly protinádorové kombinované chemoterapie farmakologie terapeutické užití škodlivé účinky MeSH
- pyrazoly farmakologie MeSH
- pyrimidiny MeSH
- synergismus léků * MeSH
- viabilita buněk účinky léků MeSH
- xenogenní modely - testy protinádorové aktivity * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- resmetirom,
- MeSH
- jaterní cirhóza farmakoterapie MeSH
- lidé MeSH
- nealkoholová steatóza jater * farmakoterapie patologie MeSH
- pyridaziny MeSH
- tyreoidální hormony, receptory beta agonisté MeSH
- uracil analogy a deriváty MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- komentáře MeSH
- souhrny MeSH
Pokročilý karcinom prostaty (KP) má relativně často změny v genech, které se účastní opravy DNA. V tom případě můžeme opravu zlomů DNA zablokovat pomocí inhibitorů poly(adenosindifosfát-ribóza)polymerázy (PARP). Nejvíce dat máme o účinnosti inhibitoru PARP olaparibu, který je možné podat pacientům s metastatickým kastračně rezistentním KP (mCRPC) a pozitivitou mutace BRCA1/2 po předchozí léčbě abirateronem nebo enzalutamidem. Druhou indikaci představuje kombinace olaparibu s abirateronem v 1. linii léčby mCRPC (bez nutnosti genetického testování), pokud není klinicky indikována chemoterapie. Talazoparib můžeme podat v kombinaci s enzalutamidem pacientům s mCRPC, u kterých také není indikována chemoterapie. Testování nádorových mutací není vyžadováno. Obdobně také niraparib v kombinaci s abirateronem můžeme použít u pacientů s mCRPC a mutacemi genu BRCA1/2, u kterých nezvažujeme chemoterapii. Výsledky v léčbě mCRPC má ještě rukaparib, který v České republice zatím není možné mužům s KP podávat.
Advanced prostate cancer (PC) relatively often has alterations in genes involved in DNA repair. In that case, we can block the repair of DNA breaks using poly-adenosine diphosphate-ribose-polymerase (PARP) inhibitors. The most studied PARP inhibitor is olaparib, which can be given to patients with metastatic castration-resistant PC (mCRPC) and a positive BRCA1/2 mutation after previous treatment with abiraterone or enzalutamide. The next indication is the combination of olaparib with abiraterone in the firstline treatment of mCRPC (without the need for genetic testing), if chemotherapy is not clinically indicated. Talazoparib can be given in combination with enzalutamide to patients with mCRPC who are also not indicated for chemotherapy. Tumor mutation testing is not required. Similarly, we can also use niraparib in combination with abiraterone in patients with mCRPC and BRCA1/2 gene mutations, if chemotherapy is not considered. Also rucaparib has results in the treatment of mCRPC, but is not yet available for men with PC in the Czech Republic.
Disruption of the thyroid hormone (TH) system is connected with diverse adverse health outcomes in wildlife and humans. It is crucial to develop and validate suitable in vitro assays capable of measuring the disruption of the thyroid hormone (TH) system. These assays are also essential to comply with the 3R principles, aiming to replace the ex vivo tests often utilised in the chemical assessment. We compared the two commonly used assays applicable for high throughput screening [Luminol and Amplex UltraRed (AUR)] for the assessment of inhibition of thyroid peroxidase (TPO, a crucial enzyme in TH synthesis) using several cell lines and 21 compounds from different use categories. As the investigated cell lines derived from human and rat thyroid showed low or undetectable TPO expression, we developed a series of novel cell lines overexpressing human TPO protein. The HEK-TPOA7 model was prioritised for further research based on the high and stable TPO gene and protein expression. Notably, the Luminol assay detected significant peroxidase activity and signal inhibition even in Nthy-ori 3-1 and HEK293T cell lines without TPO expression, revealing its lack of specificity. Conversely, the AUR assay was specific to TPO activity. Nevertheless, despite the different specificity, both assays identified similar peroxidation inhibitors. Over half of the tested chemicals with diverse structures and from different use groups caused TPO inhibition, including some widespread environmental contaminants suggesting a potential impact of environmental chemicals on TH synthesis. Furthermore, in silico SeqAPASS analysis confirmed the high similarity of human TPO across mammals and other vertebrate classes, suggesting the applicability of HEK-TPOA7 model findings to other vertebrates.
- MeSH
- autoantigeny metabolismus MeSH
- buněčné linie MeSH
- endokrinní disruptory toxicita MeSH
- HEK293 buňky MeSH
- jodidperoxidasa * antagonisté a inhibitory metabolismus genetika MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- luminol MeSH
- oxaziny MeSH
- proteiny vázající železo metabolismus MeSH
- rychlé screeningové testy metody MeSH
- štítná žláza účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
PROpel je dvojitě zaslepená klinická studie fáze III, která dosáhla primárního cíle v parametru signifikantního prodloužení přežití bez radiografické progrese onemocnění a celkového přežití při léčbě kombinací olaparib a abirateron oproti kombinaci placebo + abirateron. Výsledky subanalýz podporují doporučení této kombinace do první linie léčby metastazujícího kastračně rezistentního karcinomu prostaty i u pacientů bez mutace BRCA.
PROpel is a phase III double-blind trial, met its primary endpoint with a significant radiographic progression free survival and overall survival benefit with olaparib + abiraterone vs. placebo + abiraterone. The results of sub-analysis support the recommendation of this combination also in non-BRCA mutant patients in first line treatment metastatic castration resistant prostate cancer.
- Klíčová slova
- studie PROpel, olaparib, non-BRCA mutace,
- MeSH
- abirateron farmakologie terapeutické užití MeSH
- doba přežití bez progrese choroby MeSH
- ftalaziny farmakologie terapeutické užití MeSH
- geny BRCA1 MeSH
- lidé MeSH
- metastázy nádorů farmakoterapie MeSH
- mutace MeSH
- nádory prostaty rezistentní na kastraci * farmakoterapie genetika patologie MeSH
- piperaziny aplikace a dávkování farmakologie terapeutické užití MeSH
- protokoly protinádorové kombinované chemoterapie * MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- klinické zkoušky, fáze III MeSH
- MeSH
- bcr-abl fúzní proteiny genetika MeSH
- blastická krize * genetika farmakoterapie patologie MeSH
- chronická myeloidní leukemie * farmakoterapie genetika patologie MeSH
- imidazoly * terapeutické užití aplikace a dávkování MeSH
- inhibitory proteinkinas terapeutické užití farmakologie MeSH
- lidé MeSH
- mutace * MeSH
- myši MeSH
- niacinamid analogy a deriváty MeSH
- protokoly protinádorové kombinované chemoterapie terapeutické užití MeSH
- pyrazoly MeSH
- pyridaziny * terapeutické užití aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- dopisy MeSH
BACKGROUND: The PROpel study (NCT03732820) demonstrated a statistically significant progression-free survival benefit with olaparib plus abiraterone versus placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer (mCRPC) setting, irrespective of homologous recombination repair mutation status. OBJECTIVE: We report additional safety analyses from PROpel to increase clinical understanding of the adverse-event (AE) profiles of olaparib plus abiraterone versus placebo plus abiraterone. DESIGN, SETTING, AND PARTICIPANTS: A randomised (1:1), double-blind, placebo-controlled trial was conducted at 126 centres in 17 countries (October 2018-January 2020). Patients had mCRPC and no prior systemic mCRPC treatment. INTERVENTION: Olaparib (300 mg bid) or placebo with abiraterone (1000 mg od) plus prednisone/prednisolone (5 mg bid). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The data cut-off date was July 30, 2021. Safety was assessed by AE reporting (Common Terminology Criteria for Adverse Events v4.03) and analysed descriptively. RESULTS AND LIMITATIONS: The most common AEs (all grades) for olaparib plus abiraterone versus placebo plus abiraterone were anaemia (46.0% vs 16.4%), nausea (28.1% vs 12.6%), and fatigue (27.9% vs 18.9%). Grade ≥3 anaemia occurred in 15.1% versus 3.3% of patients in the olaparib plus abiraterone versus placebo plus abiraterone arm. The incidences of the most common AEs for olaparib plus abiraterone peaked early, within 2 mo, and were managed typically by dose modifications or standard medical practice. Overall, 13.8% versus 7.8% of patients discontinued treatment with olaparib plus abiraterone versus placebo plus abiraterone because of an AE; 3.8% versus 0.8% of patients discontinued because of anaemia. More venous thromboembolism events were observed in the olaparib plus abiraterone arm (any grade, 7.3%; grade ≥3, 6.8%) than in the placebo plus abiraterone arm (any grade, 3.3%; grade ≥3, 2.0%), most commonly pulmonary embolism (6.5% vs 1.8% for olaparib plus abiraterone vs placebo plus abiraterone). CONCLUSIONS: Olaparib plus abiraterone has a manageable and predictable safety profile. PATIENT SUMMARY: The PROpel trial showed that in patients who had not received any previous treatment for metastatic castration-resistant prostate cancer, olaparib combined with abiraterone was more effective in delaying progression of the disease than abiraterone alone. Most side effects caused by combining olaparib with abiraterone could be managed with supportive care methods, by pausing olaparib administration for a short period of time and/or by reducing the dose of olaparib.
- MeSH
- androsteny * terapeutické užití aplikace a dávkování škodlivé účinky MeSH
- dvojitá slepá metoda MeSH
- ftalaziny * terapeutické užití škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádory prostaty rezistentní na kastraci * farmakoterapie patologie MeSH
- piperaziny * terapeutické užití aplikace a dávkování škodlivé účinky MeSH
- protokoly protinádorové kombinované chemoterapie * terapeutické užití MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- Klíčová slova
- tepotinib,
- MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- mukoepidermoidní karcinom * diagnóza patologie terapie MeSH
- nádory kostí farmakoterapie sekundární MeSH
- nádory plic diagnóza patologie terapie MeSH
- piperidiny farmakologie MeSH
- protokoly protinádorové léčby MeSH
- pyridaziny farmakologie MeSH
- pyrimidiny farmakologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Tepotinib je perorální inhibitor tyrosinkinázového receptoru MET, jenž prokázal aktivitu u nádorů se skipping mutací MET v exonu 14, kterou v současné době můžeme detekovat pomocí sekvenování nové generace. Tato mutace se vyskytuje asi u 3–4 % nemalobuněčných karcinomů plic (NSCLC), převážně u starších pacientů. Tepotinib rovněž prokázal aktivitu u pacientů s NSCLC s mutací EGFR a amplifikací MET jako mechanismem rezistence na osimertinib v 1. linii léčby
Tepotinib is an oral inhibitor of the MET receptor tyrosine kinase that has shown activity in tumours harbouring MET skipping mutation in exon 14, which we can currently detect using next-generation sequencing (NGS). This mutation occurs in about 3–4% of non-small-cell lung cancers (NSCLC), mostly in elderly patients. Tepotinib also demonstrated activity in NSCLC patients with EGFR mutation and MET amplification as a mechanism of resistance to osimertinib in first-line treatment.
- Klíčová slova
- tepotinib,
- MeSH
- chemorezistence MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- nemalobuněčný karcinom plic * farmakoterapie MeSH
- nežádoucí účinky léčiv MeSH
- piperidiny farmakologie MeSH
- protinádorové látky farmakologie MeSH
- pyridaziny farmakologie MeSH
- pyrimidiny farmakologie MeSH
- Check Tag
- lidé MeSH
