Inhibitory Brutonovy kinázy (BTKi) jsou první skupinou cílených léčiv, která výrazně zlepšila prognózu i kvalitu života nemocných s chronickou lymfocytární leukemií (CLL). Specifické nežádoucí účinky BTKi, zejména kardiovaskulární (KV) a krvácivé, však mohou limitovat jejich dlouhodobé užívání. Ibrutinib, BTKi první generace, byl pro nežádoucí účinky přerušen až u 26 % pacientů léčených v rámci klinických studií. I z těchto důvodů pokračují snahy o vývoj dalších generací BTKi, které by měly bezpečnější profil při zachovaném protinádorovém účinku. Patří mezi ně kovalentně se vázající BTKi akalabrutinib a zanubrutinib a reverzibilní, nekovalentní BTK inhibitory pirtobrutinib a nemtabrutinib. V České republice je v současnosti z veřejného zdravotního pojištění hrazen akalabrutinib. V rámci prevence KV komplikací je zásadní stanovení KV rizika u konkrétního pacienta; pro tyto potřeby lze využít jednoduché skórovací systémy typu Framinghamského skóre nebo tabulky SCORE. U nemocných s vysokým KV rizikem je doporučována léčba BTKi 2. generace nebo léky ze skupiny bcl-2 inhibitorů, případně inhibitorů fosfatidylinositol-3-kinázy. Pokud dojde k rozvoji fibrilace síní nebo srdečního selhání, je nezbytná spolupráce s kardiologem. Riziko závažného krvácení je, na rozdíl od KV komplikací, podobné u obou dostupných preparátů (2–9 % u ibrutinibu vs. 2–5 % u akalabrutinibu). V prevenci klinicky manifestního krvácení je zásadní přerušení léčby BTKi s dostatečným předstihem před každým invazivním výkonem a znovuzahájení terapie až ve chvíli, kdy je riziko krvácení již minimální. Důležitým faktorem pro snížení rizika rozvoje jakékoli komplikace je znalost stávající medikace pacienta a potenciálních lékových interakcí s BTKi. Tato práce shrnuje mechanizmus vniku kardiovaskulárních a krvácivých komplikací, jejich incidenci ve vybraných klinických studiích a doporučení pro prevenci a léčbu těchto nežádoucích účinků v běžné klinické praxi.

Bruton’s tyrosine kinase (BTK) inhibitors have altered the treatment landscape of chronic lymphocytic leukaemia (CLL). These highly eff ective drugs improve not only the prognosis but also the quality of life of CLL patients. Long-term BTK inhibitor treatment can be limited by specifi c adverse events (AEs) such as cardiovascular (CV) complications or bleeding. Ibrutinib, the fi rst-in-class BTK inhibitor, was discontinued in up to 26% of patients in clinical trials due to AEs. Therefore, there are continuing eff orts to develop BTK inhibitors with the same eff ectivity but better safety profi le, such as covalent BTKi acalabrutinib and zanubrutinib and non-covalent BTKi pirtobrutinib and nemtabrutinib. The pre-treatment workup for all patients should include CV risk level assessment using scoring systems, e. g., Framingham risk score or SCORE. In patients with high CV risk levels, next-generation BTK inhibitors or other targeted drugs (venetoclax or idelalisib) are generally preferred over ibrutinib. Patients who experience CV toxicity, particularly atrial fi brillation or heart failure, should be consulted with a cardiologist to defi ne the best treatment algorithm. In contrast to CV toxicity, the risk of major bleeding events is equal for both ibrutinib and acalabrutinib (2–9% vs. 2–5%) based on data from clinical trials. Regarding prevention of bleeding events, BTK inhibitor treatment should be appropriately held prior to any invasive procedure and cannot be restarted until the risk of bleeding is minimal. Good knowledge of the patient’s current medication and potential interactions is crucial in the prevention of any adverse event. This review describes the mechanisms of pathogenesis of cardiovascular complications and bleeding in BTK inhibitor-treated patients. It summarises their incidence in selected clinical trials and provides recommendations for managing these AEs in clinical practice.

• MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy   complications   MeSH
• Atrial Fibrillation chemically induced   prevention & control   MeSH
• Hypertension chemically induced   drug therapy   prevention & control   MeSH
• Hemorrhage * chemically induced   drug therapy   prevention & control   MeSH
• Humans MeSH
• Drug-Related Side Effects and Adverse Reactions MeSH
• Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors   adverse effects   therapeutic use   MeSH
• Heart Failure chemically induced   prevention & control   MeSH
• Check Tag
• Humans MeSH

Self-balancing diffusion is a theoretical concept that restricts the introduction of extents of reactions. This concept is analyzed in detail for general mass- and molar-based balances of reaction-diffusion mixtures, in relation to non-self-balancing cases, and with respect to its practical consequences. Self-balancing is a mathematical restriction on the divergences of diffusion fluxes. Fulfilling this condition enables the proper introduction of the extents of (independent) reactions that reduce the number of independent variables in thermodynamic descriptions. A note on a recent generalization of the concept of reaction and diffusion extents is also included. Even in the case of self-balancing diffusion, such extents do not directly replace reaction rates. Concentration changes caused by reactions (not by diffusion) are properly described by rates of independent reactions, which are instantaneous descriptors. If an overall descriptor is needed, the traditional extents of reactions can be used, bearing in mind that they include diffusion-caused changes. On the other hand, rates of independent reactions integrated with respect to time provide another overall, but reaction-only-related descriptor.

• MeSH
• Diffusion * MeSH
• Kinetics MeSH
• Thermodynamics MeSH
• Publication type
• Journal Article MeSH

Cryptococcal superinfection is a rare but potentially fatal complication, especially if its detection and subsequent treatment are delayed. Histopathological findings of pulmonary parenchyma from a deceased patient with these complications were acquired. Quite interestingly, only a minimal inflammatory reaction could be seen in an individual with no previously known immune suppression, indicating a disturbance of the immune system. This finding was well in concordance with the described changes in cellular immunity in COVID-19. We report the case of a 60 year old male with critical coronavirus disease 2019 (COVID-19) complicated by cryptococcal pneumonia and multiorgan failure. Both X-ray and CT scans revealed lung infiltrates corresponding with COVID-19 infection early after the onset of symptoms. Despite receiving standard treatment, the patient progressed into multiple organ failure, requiring mechanical ventilation, circulatory support, and haemodialysis. Cryptococcus neoformans was detected by subsequent BAL, and specific antifungal treatment was instituted. His clinical status deteriorated despite all treatment, and he died of refractory circulatory failure after 21 days from hospital admission. Histopathological findings confirmed severe diffuse alveolar damage (DAD) caused by COVID-19 and cryptococcal pneumonia. Timely diagnosis of cryptococcal superinfection may be challenging; therefore, PCR panels detecting even uncommon pathogens should be implemented while taking care of critical COVID-19 patients.

• Publication type
• Journal Article MeSH

• Keywords
• nintedanib,
• MeSH
• Adult MeSH
• Tyrosine Kinase Inhibitors * administration & dosage   adverse effects   MeSH
• Lung Diseases, Interstitial * drug therapy   MeSH
• Comorbidity MeSH
• Middle Aged MeSH
• Humans MeSH
• Drug-Related Side Effects and Adverse Reactions epidemiology   MeSH
• Aged MeSH
• Scleroderma, Systemic drug therapy   MeSH
• Vital Capacity drug effects   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH

INTRODUCTION: Probiotic administration seems to be a rational approach to promote maturation of the neonatal immune system. Mutual interaction of the microbiota with the host immune system is critical for the setting of appropriate immune responses including a tolerogenic one and thevmaintenance of homeostasis. On the other hand, our knowledge on the modes of actions of probiotics is still scarce. METHODS: In our study, probiotic strain Escherichia coli O83:K24:H31 (EcO83) was administered to neonates of allergic mothers (AMs; neonates with increased risk for allergy development) within 48 h after the delivery, and the impact of this early postnatal supplementation on allergy incidence and selected immune markers has been analyzed 10 years after the primary EcO83 administration. RESULTS: We have observed decreased allergy incidence in 10-year-old children supplemented with EcO83 (13 of 52 children were allergic) in comparison with non-supplemented children of AMs (16 of 42 children were allergic). The early postnatal EcO83 supplementation appeared to limit the allergy in the high-risk group (children of AMs) compared to that in the low-risk group (children of healthy mothers). Dendritic cells (DCs) in the peripheral blood of EcO83-supplemented children do not differ significantly in cell surface presence of CD83. The immunomodulatory capacity of EcO83 on DCs was tested in vitro as well. Both directly isolated myeloid and in vitro monocyte-derived DCs from cord blood increased CD83 expression together with interleukin (IL)-10 secretion after EcO83 stimulation. The effect of early postnatal EcO83 supplementation on the microbiota composition of 10-year-old children was characterized by next-generation sequencing, and we have not observed significant changes in the microbiota composition of EcO83-supplemented and non-supplemented children at the age of 10 years. CONCLUSIONS: Early postnatal EcO83 supplementation appears to lower allergy incidence in children of AMs. It seems that the beneficial effect of EcO83 is mediated via modulation of DC functional capacities without impacting the microbiota composition. Larger-scale studies will be necessary to confirm these preliminary findings.

• MeSH
• Hypersensitivity * epidemiology   prevention & control   MeSH
• Dendritic Cells MeSH
• Child MeSH
• Escherichia coli physiology   MeSH
• Incidence MeSH
• Humans MeSH
• Microbiota * MeSH
• Monocytes MeSH
• Infant, Newborn MeSH
• Probiotics * MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The main objective of the current research work was to synthesize mesoporous silica nanoparticles for controlled delivery of mometasone furoate for potential nasal delivery. The optimized sol-gel method was used for the synthesis of mesoporous silica nanoparticles. Synthesized nanoparticles were processed through Zeta sizer, SEM, TEM, FTIR, TGA, DSC, XRD, and BET analysis for structural characterization. The in vitro dissolution test was performed for the inclusion compound, while the Franz diffusion experiment was performed for permeability of formulation. For the determination of expression levels of anti-inflammatory cytokines IL-4 and IL-5, RNA extraction, reverse transcription, and polymerase chain reaction (RT-PCR) were performed. The MTT assay was also performed to determine cell viability. Synthesized and functionalized mesoporous silica nanoparticles showed controlled release of drugs. FT-IR spectroscopy confirmed the presence of the corresponding functional groups of drugs within mesoporous silica nanoparticles. Zeta sizer and thermal analysis confirmed the delivery system was in nano size and thermally stable. Moreover, a highly porous system was observed during SEM and TEM evaluation, and further it was confirmed by BET analysis. Greater cellular uptake with improved permeability characteristics was also observed. As compared to the crystalline drug, a significant improvement in the dissolution rate was observed. It was concluded that stable mesoporous silica nanoparticles with significant porosity were synthesized, efficiently delivering the loaded drug without any toxic effect.

• Publication type
• Journal Article MeSH

Postižení plicního intersticia provází systémovou sklerodermii často - manifestuje se až u poloviny nemocných a zároveň je nejčastější příčinou úmrtí nemocných se systémovou sklerodermií. Progresivním fenotypem by podle literárních údajů mělo trpět 8 % nemocných s intersticiálním plicním postižením při systémové sklerodermii. Poslední roky přinesly výsledky klinických studií SENSCIS a INBUILD, které prokázaly efekt nintedanibu na zpomalení poklesu usilovné vitální kapacity po roce léčby u nemocných s intersticiálním plicním postižením na podkladě systémové sklerodermie a u nemocných s progredujícím fenotypem fibrotizujících intersticiálních plicních procesů včetně těch na podkladě systémové sklerodermie. I když vedlejší účinky léčby nintedanibem (průjem) jsou obvykle zvládnutélné režimovými opatřeními a loperamidem, jsou pro pacienty nepříjemné a u nemocných se systémovou sklerodermií se vyskytují častěji než u pacientů s idiopatickou plicní fibrózou. Proto je na místě u každého pacienta individuálně posoudit potenciální benefit a rizika léčby a dle toho volit vhodný terapeutický postup.

Interstitial lung disease often accompanies systemic scleroderma and manifests itself in up to half of patients. It is also the most common cause of death in patients with systemic scleroderma. According to the literature, 8 % of patients with interstitial lung involvement due to systemic scleroderma should suffer from a progressive phenotype. Recent years have yielded the results of SENSCIS and INBUILD clinical trials, which demonstrated the effect of nintedanib in slowing the decline in forced vital capacity after one year of treatment in patients with interstitial lung disease due to systemic sclerosis and in patients with a progressive phenotype of fibrotic interstitial lung diseases including those based on systemic sclerosis. Although the side effects of nintedanib treatment (diarrhea) are usually manageable with regimens and loperamide, they are uncomfortable for patients and are more common in patients with systemic sclerosis than in patients with idiopathic pulmonary fibrosis. Therefore, it is appropriate to individually assess the potential benefits and risks of treatment for each patient and to choose the appropriate therapeutic approach accordingly.

• Keywords
• nintedanib,
• MeSH
• Indoles adverse effects   therapeutic use   MeSH
• Lung Diseases, Interstitial * drug therapy   complications   MeSH
• Clinical Trials as Topic MeSH
• Comorbidity MeSH
• Humans MeSH
• Drug-Related Side Effects and Adverse Reactions MeSH
• Pulmonary Fibrosis MeSH
• Receptors, Fibroblast Growth Factor antagonists & inhibitors   MeSH
• Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors   MeSH
• Practice Guidelines as Topic MeSH
• Scleroderma, Systemic drug therapy   complications   MeSH
• Receptor Protein-Tyrosine Kinases antagonists & inhibitors   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

The goal of the study was to design a model of cardiac ventricles with realistic geometry that enables simulation of the ventricular activation with normal conduction system functions, as well as with bundle branch blocks. In ventricles, electrical activation propagates from the His bundle to the left and right bundle branches and continues to the fascicles and branching fibers of the Purkinje system. The role of these parts of the conduction system is to lead the activation rapidly and synchronously to the left and right ventricle. The velocity of propagation in the conduction system is several times higher than in the surrounding ventricular myocardium. If the conduction system works normally, QRS duration representing the total activation time of the ventricles lies in the physiological range of about 80 to 120 ms but it is more than 120 ms in the case of bundle branch blocks. In our study, the realistic geometry of the ventricles was constructed on the base of a patient CT scan, defining epicardial and endocardial surfaces. The first part of the conduction system (fast-conducting bundle branches, fascicles in the left ventricle and initial parts of the Purkinje fibers) was modeled as polyline pathways isolated from the surrounding ventricular tissue. The remaining part of the Purkinje system was modeled as an endocardial layer with higher conduction velocity. The propagation of the electrical activation in the ventricular model was modeled using reaction-diffusion (RD) equations, except for the first part of the conduction system, where the activation times were evaluated algebraically with respect to predefined velocity of propagation and estimated distance between the His bundle and particular entry point to the layer with higher conduction velocity. Propagation of activation in cardiac ventricles was numerically solved in Comsol Multiphysics environment. Several configurations of the first part of the conduction system with different number of polyline pathways and entry points were proposed and tested to achieve realistic activation propagation. For the model with 9 starting points, realistic total activation time (TAT) of the whole ventricles of about 108 ms was obtained for the model with normal conduction system, and realistic TAT of 126 ms and 149 ms were obtained for the right and left bundle branch block (RBBB, LBBB), respectively. Very similar TAT was found also for the model with 7 starting points, but unrealistically long TAT was obtained in LBBB simulation for the model with only 5 starting points.

• MeSH
• Models, Anatomic MeSH
• Biomedical Technology methods   MeSH
• Biomedical Research instrumentation   trends   MeSH
• Bundle-Branch Block * diagnostic imaging   physiopathology   MeSH
• Humans MeSH
• Models, Cardiovascular MeSH
• Computer Simulation classification   MeSH
• Heart Ventricles anatomy & histology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Ibuprofen (IBU) is a non-steroidal anti-inflammatory drug (NSAID) commonly used in the treatment of pain, fever and inflammation. However, the administration of IBU in its free carboxylic acid form is strongly dependent on its limited solubility in aqueous solution. This mandates for an increased drug concentration to reach the therapeutic window, and promotes the alternative use of IBU sodium salt, even if this latter form poses significant constraints in terms of tunable release due to its uncontrolled and rapid diffusion. A potential solution is represented by oral administration through physical encapsulation of ibuprofen in designed carriers, despite this route limits the application of this therapeutic agent. In this work, we propose the covalent tethering of ibuprofen to a hydrogel matrix via esterification reaction. Exploiting the cleavability of the ester bond under physiological conditions, we propose a controlled drug delivery system where the whole drug payload can be released, thus overcoming the questioned aspects of over-dosage and solubility-dependent administration. In particular, we tested the biological activity of cleaved ibuprofen in terms of cyclooxygenase inhibition, reporting that chemical tethering did not alter the efficiency of the NSAID. Moreover, due to the sol-gel transition of the hydrogel matrix, these ibuprofen-functionalized hydrogels could be used as injectable tools in several clinical scenarios, performing a localized drug release and opening advanced avenues for in situ treatments.

• MeSH
• Acrylic Resins chemistry   MeSH
• Administration, Oral MeSH
• Prostaglandin-Endoperoxide Synthases metabolism   MeSH
• Enzyme Assays MeSH
• Hydrogels chemistry   MeSH
• Ibuprofen administration & dosage   pharmacokinetics   MeSH
• Cyclooxygenase Inhibitors administration & dosage   pharmacokinetics   MeSH
• Delayed-Action Preparations administration & dosage   pharmacokinetics   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Drug Carriers chemistry   MeSH
• Propylene Glycols chemistry   MeSH
• Solubility MeSH
• Sepharose chemistry   MeSH
• Drug Liberation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Durvalumab je plně humanizovaná IgGκ monoklonální protilátka, která selektivně blokuje ligand receptoru programované buněčné smrti (PD‑L1). V Evropské unii je registrován ke konsolidační léčbě lokálně pokročilého inoperabilního nemalobuněčného karcinomu plic (NSCLC) bez progrese po chemoradiační terapii (CRT).

Durvalumab is a fully humanized IgGκ monoclonal antibody that selectively blocks programmed cell death ligand 1 (PD‑L1). In European Union, it is registered for consolidation treatment of non‑small cell lung cancer (NSCLC) which has not progressed following platinum‑based chemoradiation therapy (CRT).

• Keywords
• durvalumab,
• MeSH
• B7-H1 Antigen antagonists & inhibitors   immunology   MeSH
• Autoimmune Diseases chemically induced   etiology   MeSH
• Immune Checkpoint Inhibitors * pharmacology   adverse effects   therapeutic use   MeSH
• Lung Diseases, Interstitial chemically induced   etiology   drug therapy   MeSH
• Colitis chemically induced   etiology   drug therapy   MeSH
• Drug Eruptions etiology   drug therapy   MeSH
• Chemical and Drug Induced Liver Injury etiology   drug therapy   MeSH
• Humans MeSH
• Antibodies, Monoclonal pharmacokinetics   adverse effects   therapeutic use   MeSH
• Nephritis chemically induced   etiology   drug therapy   MeSH
• Carcinoma, Non-Small-Cell Lung * drug therapy   MeSH
• Endocrine System Diseases chemically induced   etiology   drug therapy   MeSH
• Drug-Related Side Effects and Adverse Reactions etiology   drug therapy   MeSH
• Check Tag
• Humans MeSH