In this systematic review, we report on the effects of diuretic deprescribing compared to continued diuretic use. We included clinical studies reporting on outcomes such as mortality, heart failure recurrence, tolerability and feasibility. We assessed risk of bias and certainty of the evidence using the GRADE framework. We included 25 publications from 22 primary studies (15 randomized controlled trials; 7 nonrandomized studies). The mean number of participants in the deprescribing groups was 35, and median/mean age 64 years. In patients with heart failure, there was no clear evidence that diuretic deprescribing was associated with increased mortality compared to diuretic continuation (low certainty evidence). The risk of cardiovascular composite outcomes associated with diuretic deprescribing was inconsistent (studies showing lower risk for diuretic deprescribing, or comparable risk with diuretic continuation; very low certainty evidence). The effect on heart failure recurrence after diuretic deprescribing in patients with diuretics for heart failure, and of hypertension in patients with diuretics for hypertension was inconsistent across the included studies (low certainty evidence). In patients with diuretics for hypertension, diuretic deprescribing was well tolerated (moderate certainty evidence), while in patients with diuretics for heart failure, deprescribing diuretics can result in complaints of peripheral oedema (very low certainty evidence). The overall risk of bias was generally high. In summary, this systematic review suggests that diuretic discontinuation could be a safe and feasible treatment option for carefully selected patients. However, there isa lack of high-quality evidence on its feasibility, safety and tolerability of diuretic deprescribing, warranting further research.

• MeSH
• depreskripce * MeSH
• diuretika * škodlivé účinky   aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• hypertenze farmakoterapie   MeSH
• lidé MeSH
• medicína založená na důkazech MeSH
• randomizované kontrolované studie jako téma MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• srdeční selhání * farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• systematický přehled MeSH

Projekt bude zaměřen na studium metabolických pochodů u pacientů s Alzheimerovou nemocí (AD) ve srovnání se změnami u zdravých seniorů. Z opakovaného vyšetření seniorů v 5-ti letém intervalu určíme, které změny námi sledovaných neuroaktivních biomarkerů doprovází přirozené stárnutí a které charakterizují patologické stárnutí. Cílem projektu bude zpřesnit prediktivní model pro identifikaci osob v riziku AD, zjednodušit a klinické praxi přiblížit dostupnost tohoto modelu. Náš přístup otevírá možnosti včasné farmakologické nebo preventivní intervence zacílené na konkrétní metabolickou dráhu. Význam plánovaného modelu spočívá v možnosti využít pro predikci onemocnění dostupnou tkáň - periferní krev. Projekt je naplánován jako pokračování předešlého projektu "Studium společných patogenetických faktorů Alzheimerovy choroby a diabetes mellitus 2. typu" (IGA MZČR NT13543-4). Projekt naváže na průběžné výsledky prokazující rozdíly v glukózové toleranci, v hladinách cirkulujících neuroaktivních steroidů a v hladinách některých cytokinů, adipokinů a inkretinů u AD oproti zdravým kontrolám.; The project will focus on metabolic processes in patients with Alzheimer’s disease (AD) compared to healthy seniors. Repeated examination of the subjects at 5-year interval should reveal which changes of the examined neuroactive biomarkers accompany natural aging, and which are associated with pathological aging. The aim of the study is to make a prediction model able to identify persons at risk of AD more precisely, to simplify the prediction model and make it applicable to clinical practice, thanks to detection of neuroactive biomarkers in peripheral blood. This approach opens the opportunity of early pharmacologic or preventive intervention focused on certain metabolic pathway. The project is proposed as continuation and completion of previous project “Study of Common Pathogenetic Factors in Alzheimer’s Disease and Type 2 Diabetes Mellitus” (IGA MZ ČR NT13543-4). It will build on the current results proving differences in glucose tolerance, concentrations of circulating neuroactive steroids, some cytokines, adipokines and incretins in AD compared to healthy subjects.

• Klíčová slova
• cytokiny, cytokines, inkretiny, adipokiny, incretins, adipokines, Alzheimerova nemoc, neurosteroidy, vícerozměrná regrese, Alzheimer's disease, neurosteroids, multidimensional regression,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

Implantace totální kloubní náhrady je jednou z nejúspěšnějších a nejúčinnějších ortopedických operací v posledním století. V tomto projektu chceme monitorovat a porovnávat zátěž těžkými kovy v cirkulaci, zejména Ti, Co, Cr, Ni, u pacientů po implantaci kloubní náhrady ve srovnání s populací České republiky bez implantátů jakéhokoliv kovu. Korelace dynamiky hojení a tolerance kovového materiálu bude hodnocena s klinickou symptomatologií, funkčními parametry s ohledem na vývoj a průběh komplikací po implantaci endoprotéz, včetně reimplantace. Procesy spojené s aktivací imunitního systému, včetně reakcí přecitlivělosti, budou simulovány na modelu in vitro za použití imunitního systému individuálního pacienta. Pokus o nalezení prediktivních markerů spojených se špatnou prognózou po implantaci v periferní krvi by mohl vést k včasnému zjištění komplikací. Povrch explantovaných náhrad bude hodnocen z hlediska opotřebení, koroze, defektů kovu.; Total-joint arthroplasty is one of the most successful and effective orthopedic operations performed during the last century. In the present project, we intend to monitor and compare heavy metal load in circulation, especially Ti, Co, Cr, Ni, in patients after implantation of joint replacement compared to the Czech Republic without implants of any metal. The correlation of the healing process dynamics and the tolerance of the metal material will be evaluated with clinical symptomatology, functional parameters with respect to the development and course of complications after implantation of the endoprostheses, including reimplantation. Processes associated with the activation of the immune system, including hypersensitivity reactions, will be simulated on an in vitro model using individual patient immune systems. Attempting to find predictive markers associated with poor prognosis after implantation in peripheral blood could lead to early detection of complications. The metal surface of the explanted substitutes will be evaluated in terms of wear, corrosion, metal defects.

• Klíčová slova
• implantace, hypersenzitivita, implantation, hypersensitivity, kov, metal, imunitní systém, Osteoartróza, totální kloubní náhrada, osteoblasty, osteoarthrosis, total joint arthroplasty, immmune system, osteoblasts, reimplantace, reimplantation,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a peripheral nerve disorder characterised by weakness and sensory loss. We assessed the neonatal Fc receptor inhibitor rozanolixizumab for CIDP management. METHODS: CIDP01 (NCT03861481) was a randomised, subject-blind, investigator-blind, placebo-controlled, phase 2a study. Adults with definite or probable CIDP receiving subcutaneous or intravenous immunoglobulin maintenance therapy were randomised 1:1 to 12 once-weekly subcutaneous infusions of rozanolixizumab 10 mg/kg or placebo, stratified according to previous immunoglobulin administration route. Investigators administering treatment and assessing efficacy, and patients, were blinded. The primary outcome was a change from baseline (CFB) to day 85 in inflammatory Rasch-built Overall Disability Scale (iRODS) score. Eligible patients who completed CIDP01 entered the open-label extension CIDP04 (NCT04051944). RESULTS: In CIDP01, between 26 March 2019 and 31 March 2021, 34 patients were randomised to rozanolixizumab or placebo (17 (50%) each). No significant difference in CFB to day 85 in iRODS centile score was observed between rozanolixizumab (least squares mean 2.0 (SE 3.2)) and placebo (3.4 (2.6); difference -1.5 (90% CI -7.5 to 4.5)). Overall, 14 (82%) patients receiving rozanolixizumab and 13 (76%) receiving placebo experienced a treatment-emergent adverse event during the treatment period. Across CIDP01 and CIDP04, rozanolixizumab was well tolerated over up to 614 days; no clinically meaningful efficacy results were seen. No deaths occurred. CONCLUSIONS: Rozanolixizumab did not show efficacy in patients with CIDP in this study, although this could be due to a relatively high placebo stability rate. Rozanolixizumab was well tolerated over medium-to-long-term weekly use, with an acceptable safety profile.

• MeSH
• chronická zánětlivá demyelinizační polyneuropatie * farmakoterapie   MeSH
• dospělí MeSH
• humanizované monoklonální protilátky * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• intravenózní imunoglobuliny terapeutické užití   škodlivé účinky   MeSH
• jednoduchá slepá metoda MeSH
• lidé středního věku MeSH
• lidé 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
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

Peripheral neuropathy is one of the most common neurological diseases of the peripheral nervous system. According to current statistics, it affects 2.4% of the Czech population, and its prevalence continues to increase with age. The possibilities of its treatment are to a large extent limited, and its effectiveness and the patient's tolerance of pharmacotherapy are individual. Neurotropic vitamins, which support the function of neurons and contribute to their protection and regeneration, represent a promising possibility for prevention and use in adjuvant therapy for patients suffering from this disease. Despite the fact that the diagnosis and treatment of peripheral neuropathy belong to the doctor, the role of the pharmacist can be crucial not only in the area of ensuring effective and safe pharmacotherapy and adherence to it, but also in pre-screening of at-risk persons visiting pharmacies. The primary aim of the article is therefore to familiarize readers with the significance of neurotropic vitamins in the prevention and adjunct therapy of peripheral neuropathy, as well as the role of the pharmacist in the care of patients suffering from this condition.

• MeSH
• farmakoterapie metody   MeSH
• lidé MeSH
• nedostatek vitaminu B12 komplikace   MeSH
• nemoci periferního nervového systému * etiologie   farmakoterapie   prevence a kontrola   MeSH
• vitamin B 12 farmakologie   terapeutické užití   MeSH
• vitamin B6 farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

The topic of human circadian rhythms is not only attracting the attention of clinical researchers from various fields but also sparking a growing public interest. The circadian system comprises the central clock, located in the suprachiasmatic nucleus of the hypothalamus, and the peripheral clocks in various tissues that are interconnected; together they coordinate many daily activities, including sleep and wakefulness, physical activity, food intake, glucose sensitivity and cardiovascular functions. Disruption of circadian regulation seems to be associated with metabolic disorders (particularly impaired glucose tolerance) and cardiovascular disease. Previous clinical trials revealed that disturbance of the circadian system, specifically due to shift work, is associated with an increased risk of type 2 diabetes mellitus. This review is intended to provide clinicians who wish to implement knowledge of circadian disruption in diagnosis and strategies to avoid cardio-metabolic disease with a general overview of this topic.

• MeSH
• chronobiologické poruchy patofyziologie   komplikace   MeSH
• cirkadiánní rytmus * fyziologie   MeSH
• diabetes mellitus 2. typu patofyziologie   metabolismus   MeSH
• kardiovaskulární nemoci * etiologie   patofyziologie   MeSH
• lidé MeSH
• metabolické nemoci * patofyziologie   metabolismus   etiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Since its discovery, Aire has been the topic of numerous studies in its role as a transcriptional regulator in the thymus where it promotes the "promiscuous" expression of a large repertoire of tissue-restricted antigens (TRAs) that are normally expressed only in the immune periphery. This process occurs in specialized medullary thymic epithelial cells (mTECs) and mediates the elimination of self-reactive T cells or promotes their conversion to the Foxp3+ regulatory T cell lineage, both of which are required for the prevention of autoimmunity. In recent years, there has been increasing interest in the role of extrathymic Aire expression in peripheral organs. The focus has primarily been on the identification of the cellular source(s) and mechanism(s) by which extrathymic AIRE affects tolerance-related or other physiological processes. A cadre of OMICs tools including single cell RNA sequencing and novel transgenic models to trace Aire expression to perform lineage tracing experiments have shed light on a phenomenon that is more complex than previously thought. In this chapter, we provide a deeper analysis of how extrathymic Aire research has developed and progressed, how cellular sources were identified, and how the function of AIRE was determined. Current data suggests that extrathymic AIRE fulfills a function that differs from what has been observed in the thymus and strongly argues that its main purpose is to regulate transcriptional programs in a cell content-dependent manner. Surprisingly, there is data that also suggests a non-transcriptional role of extrathymic AIRE in the cytoplasm. We have arrived at a potential turning point that will take the field from the classical understanding of AIRE as a transcription factor in control of TRA expression to its role in immunological and non-immunological processes in the periphery.

• MeSH
• antigeny MeSH
• autoimunita MeSH
• epitelové buňky metabolismus   MeSH
• regulace genové exprese * MeSH
• thymus MeSH
• transkripční faktory * genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Melflufen, a first-in-class alkylating peptide-drug conjugate, rapidly enters tumor cells and metabolizes to melphalan. In previous studies, melflufen was administered via central venous catheter (CVC). However, administration by peripheral venous catheter (PVC) may be preferable. PATIENTS AND METHODS: PORT was a two-period, phase 2 crossover study of CVC versus PVC melflufen administration in patients with relapsed/refractory multiple myeloma. Adults with ≥ 2 prior therapies refractory to/intolerant of an immunomodulatory drug and a proteasome inhibitor were randomized 1:1 to weekly oral dexamethasone plus melflufen (40 mg) via CVC or PVC infusion on day 1 of 28-day cycle 1. In cycle 2, patients continued dexamethasone and crossed over to the other melflufen administration route. In cycle 3, all patients received melflufen until progression; PVC or CVC routes were allowed based upon investigator decision. Pharmacokinetic sampling was performed during and after melflufen infusion. Primary endpoints were melphalan pharmacokinetic parameters (Cmax, AUC(0-t), and AUC(0-∞)) and frequency and severity of PVC-related local reactions. RESULTS: The 90% CIs for adjusted geometric mean ratios for pharmacokinetic parameters following CVC versus PVC administration were within the 0.8-1.25 bioequivalence range (Cmax 0.946 [90% CI: 0.849, 1.053]; AUC(0-t) 0.952 [90% CI: 0.861, 1.053]; AUC(0-∞) 0.955 [90% CI: 0.863, 1.058]). In both arms, adverse events were primarily hematological and similar; no phlebitis or local infusion-related reactions occurred. CONCLUSION: Melflufen PVC and CVC administrations are bioequivalent based on melphalan pharmacokinetic parameters. Melflufen via PVC was well tolerated, with no infusion-related reactions or new safety signals and may represent an alternative route of administration.

• MeSH
• dospělí MeSH
• fenylalanin analogy a deriváty   aplikace a dávkování   farmakokinetika   MeSH
• intravenózní infuze MeSH
• intravenózní podání MeSH
• klinické křížové studie * MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• melfalan aplikace a dávkování   terapeutické užití   analogy a deriváty   MeSH
• mnohočetný myelom * farmakoterapie   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

Axiální spondyloartritida je chronické revmatické onemocnění postihující osový skelet, periferní klouby a mimokloubní struktury. Cílem léčby je potlačit zánětlivou aktivitu a zabránit strukturálnímu poškození, aby se minimalizovala bolest a ztuhlost a zachovala pohyblivost a dobrá kvalita života pacientů. Interleukiny (IL) 17A a 17F jsou prozánětlivé cytokiny, které hrají důležitou roli v patogenezi axiální spondyloartritidy. IL-17F je u pacientů s axiální spondyloartritidou zvýšeně exprimován, i když je biologicky méně aktivní než IL-17A. Nicméně kombinovaná inhibice obou těchto cytokinů ukázala v in vitro experimentech lepší účinnost ve snižování zánětlivé aktivity než samostatná inhibice jednoho z nich. Bimekizumab je první monoklonální protilátka, která selektivně tlumí interakci IL-17A i IL-17F s jejich receptory. V klinických hodnoceních byla prokázána jeho účinnost a bezpečnost u pacientů s axiální spondyloartritidou. Pacienti, kteří užívali bimekizumab, dosáhli signifikantně lepší klinické odpovědi podle kritérií ASAS (Assessment of SpondyloArthritis International Society) a výraznějšího zmírnění objektivních ukazatelů zánětu než pacienti užívající placebo. Léčba byla účinná nezávisle na předchozí terapii a bimekizumab byl obecně dobře snášen. Mezi nejčastější nežádoucí účinky patřily nasofaryngitida a infekce horních cest dýchacích. Plísňové infekce byly pozorovány častěji než u placeba, ale závažné infekce a kardiovaskulární příhody byly vzácné. Bimekizumab byl na podkladě těchto klinických hodnocení schválen pro léčbu ankylozující spondylitidy, neradiografické axiální spondyloartritidy a aktivní psoriatické artritidy. Pro konstatování vyšší účinnosti kombinované inhibice IL-17A a IL-17F u spondyloartritid, jako bylo prokázáno u psoriázy, zatím chybí srovnávací klinická hodnocení. Celkově lze konstatovat, že bimekizumab je účinný a dobře snášený biologický lék pro pacienty s axiální spondyloartritidou a představuje novou naději v léčbě tohoto onemocnění.

Axial spondyloarthritis is a chronic rheumatic disease affecting the axial skeleton, peripheral joints and extraarticular structures. The goal of treatment is to suppress inflammatory activity and prevent structural damage in order to minimize pain and stiffness and to preserve mobility and good quality of life of the patients. Interleukins (IL) 17A and 17F are pro-inflammatory cytokines that play an important role in the pathogenesis of axial spondyloarthritis. IL-17F is elevatedly expressed in patients with axial spondyloarthritis, although it is biologically less active than IL-17A. However, combined inhibition of both of these cytokines has shown better efficacy in reducing inflammatory activity in in vitro experiments than inhibition of either cytokine alone. Bimekizumab is the first monoclonal antibody that selectively inhibits the interaction of both IL-17A and IL-17F with their receptors. Its efficacy and safety have been demonstrated in clinical trials in patients with axial spondyloarthritis. Patients treated with bimekizumab achieved a significantly greater improvement in ASAS (Assessment of SpondyloArthritis International Society) clinical response and reduction in objective markers of inflammation than patients taking placebo. Treatment was effective independently of prior therapy and bimekizumab was generally well tolerated. The most common adverse effects were nasopharyngitis and upper respiratory tract infections. Fungal infections were seen more frequently than in placebo arm, but serious infections and cardiovascular events were rare. Based on these clinical trials, bimekizumab was approved for the treatment of ankylosing spondylitis, non-radiographic axial spondyloarthritis and active psoriatic arthritis. Comparative clinical trials are not yet available to conclude that combined IL-17A and IL-17F inhibition is more effective in spondyloarthritis, as has been demonstrated in psoriasis. Overall, bimekizumab is an effective and well-tolerated biologic for patients with axial spondyloarthritis and represents a new hope in the treatment of this disease.

• Klíčová slova
• bimekizumab,
• MeSH
• axiální spondyloartritida * farmakoterapie   MeSH
• humanizované monoklonální protilátky farmakologie   imunologie   terapeutické užití   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH

Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation-amelogenesis1. Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta2. Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency3,4, and in patients diagnosed with coeliac disease5-7. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.

• MeSH
• ameloblasty metabolismus   MeSH
• amelogenesis imperfecta * komplikace   imunologie   MeSH
• antigeny imunologie   metabolismus   MeSH
• autoimunitní polyglandulární syndromy * komplikace   imunologie   MeSH
• autoprotilátky * imunologie   MeSH
• celiakie * komplikace   imunologie   MeSH
• imunoglobulin A imunologie   MeSH
• lidé MeSH
• protein AIRE nedostatek   MeSH
• proteiny imunologie   metabolismus   MeSH
• střeva imunologie   metabolismus   MeSH
• zubní sklovina imunologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH