V oblasti léčby hemofilie dochází v posledních letech k významnému pokroku v souvislosti s vývojem nových tzv. nefaktorových léků. Standardním postupem pro velkou část pacientů s těžkou formou choroby však zůstává a v dohledné době pravděpodobně zůstane profylaktické intravenózní podávání koncentrátu chybějícího faktoru. U takto léčených pacientů poskytuje stanovení individuální farmakokinetiky, nejlépe s využitím některého z populačních modelů, neocenitelné informace umožňující precizní nastavení a frekvence podávání léku s ohledem na míru rizika krvácení, kterému pacient při svých aktivitách čelí. Zejména vysoce aktivní část pacientů z takového přístupu může profitovat více než z nefaktorové profylaxe. I přes nepochybný rozvoj nefaktorové léčby hemofilie proto farmakokinetika bude v blízké budoucnosti i nadále neocenitelným nástrojem pro pacienta a jeho lékaře.

In recent years, there has been significant progress in the treatment of hemophilia with the development of new non-factor therapies. However, the standard approach for a significant portion of patients with severe forms of the disease remains and is likely to remain prophylactic intravenous administration of missing factor concentrate. For patients treated in this manner, determining individual pharmacokinetics, preferably using one of the population models, provides invaluable information for precise dosage and frequency of drug administration, taking into account the level of bleeding risk faced by the patient in their activities. Particularly, a highly active subset of patients can benefit more from this approach than from non-factor prophylaxis. Despite the undeniable progress in development of non-factor treatment for hemophilia, pharmacokinetics will continue to be an invaluable tool for the patient and their physician in the near future.

Poruchy krevního srážení jsou relativně vzácná onemocnění s různým stupněm klinické závažnosti, který závisí zejména na typu chybějícího koagulačního faktoru a jeho zbytkové aktivitě u konkrétního pacienta. Tento edukační článek přehledným způsobem pojednává o jednotlivých koagulačních poruchách s důrazem na hemofilii a von Willebrandovu chorobu, nastiňuje jejich etiopatogenezi, klinický obraz, diagnostiku, léčbu, komplikace a prognózu.

Blood coagulation disorders are relatively rare diseases with varying degrees of clinical severity, which mainly depends on the type of missing coagulation factor and its residual activity in a particular patient. This educational article in general summarised respective coagulation disorders with an emphasis on hemophilia and von Willebrand’s disease. Their etiopathogenesis, clinical picture, diagnosis, treatment and its complications and prognosis is outlined.

• MeSH
• dědičné koagulopatie * diagnóza   terapie   MeSH
• hemofilie A diagnóza   terapie   MeSH
• lidé MeSH
• von Willebrandova nemoc diagnóza   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Hemofilie je vrozené X-vázané krvácivé onemocnění, jehož příčinou je nedostatek koagulačního faktoru VIII (hemofilie A) či IX (hemofilie B). Současným standardem léčby její těžké formy je profylaktické intravenózní podávání koncentrátu chybějícího faktoru. Dávkování se stanovuje totožným způsobem pro všechny osoby s hemofilií a následně se empiricky upravuje podle pacientova krvácivého fenotypu. Vzhledem k významné interindividuální variabilitě v odpovědi na podávaný lék se však tento přístup dnes jeví již jako překonaný. Současný trend se jednoznačně ubírá směrem k individualizaci a personalizaci terapie, jedním z hlavních způsobů individualizace léčby hemofilie je farmakokinetický přístup. Farmakokinetika podaného koncentrátu poskytuje detailní a pro daného jedince specifické informace o efektu léčby. Na jejím základě lze podle potřeby upravit léčebné schéma – interval léčby, její dávkování, případně i výběr přípravku. Vzhledem k náročnosti stanovení farmakokinetických parametrů klasickým způsobem se v současnosti dynamicky rozvíjí disciplína populační farmakokinetiky. Díky sofistikovaným populačním modelům lze vytvořit odhad individuální farmakokinetiky každého pacienta i z velmi omezeného počtu vzorků získaných v různých situacích. Modely populační farmakokinetiky jsou pro klinické pracovníky dostupné prostřednictvím internetového rozhraní. Kromě stanovení individuální farmakokinetiky tyto modely dále umožňují zhodnotit efektivitu stávající léčby a vygenerovat nový dávkovací režim na základě zadaných parametrů (četnost aplikací, prahová hladina faktoru, dávka). Ve vývoji jsou v současnosti i mobilní aplikace, které umožní každému pacientovi získat přehled o aktuální hladině faktoru. Díky těmto informacím bude pacient moci zhodnotit, zda je určitá činnost vhodná v daný moment, a své aktivity dopředu plánovat v závislosti na míře ochrany před krvácením.

Haemophilia is an inborn X-linked bleeding disorder, which is caused by a deficiency of coagulation factor VIII in haemophilia A and factor IX in haemophilia B. Currently, the standard treatment regimen for severe forms of the disease is the prophylactic intravenous administration of the deficient factor. The initial dosage is assessed identically for all persons with haemophilia and subsequently modified empirically depending on the individual bleeding phenotype. Due to the large inter-individual variability in the response, to the administered factor, this „one-size-fits-all “approach is now deemed obsolete. Treatment individualization and personalization is gaining in importance. One of the most important ways to individualize treatment is using a pharmacokinetic approach. Pharmacokinetics of the administered concentrate provide to detailed and individually specific information regarding treatment efficacy. Based on pharmacokinetics, it is possible to adjust treatment – dose, frequency of infusions and even the choice of factor concentrate. It is complicated to perform a classic pharmacokinetic assessment, which is why a population pharmacokinetic approach is becoming more and more attractive. Using sophisticated population models, it is possible to assess the individual pharmacokinetics from the limited number of samples obtained in different situations. Population pharmacokinetic models are easily available for clinicians as internet-based applications. Apart from assessing the individual pharmacokinetics, they can be used to evaluate the efficacy of the current dosing regimen and generate a new one based on the required frequency of application, trough level or dose. Mobile applications, which will allow each patient to gain access, to his/her current factor level are being developed. With this knowledge, a haemophiliac will be able to assess the suitability of a planned activity at any given moment and schedule their activities in advance according to the estimated protection level.

• Klíčová slova
• populační farmakokinetika,
• MeSH
• farmakokinetika MeSH
• hemofilie A * farmakoterapie   MeSH
• individualizovaná medicína MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

BACKGROUND: Various antiplatelet drugs are used following Acute Coronary Syndromes (ACS). Of them, adenosine diphosphate receptor P2Y12 inhibitors clopidogrel, prasugrel and ticagrelor are currently used for post-ACS long-term treatment. Although they act on the same receptor, they differ in pharmacodynamics and pharmacokinetics. Several enzymes and transporters involved in the metabolism of P2Y12 inhibitors show genetic variability with functional impact. This includes Pglycoprotein, carboxylesterase 1 and, most notably, CYP2C19 that is important in clopidogrel activation. Common gain-of-function or loss-of-function alleles of CYP2C19 gene are associated with lower or higher platelet reactivity that may impact clinical outcomes of clopidogrel treatment. Prasugrel is considered to be less dependent on CYP2C19 variability as it is also metabolized by other CYP450 isoforms. Some studies, however, showed the relevance of CYP2C19 variants for platelet reactivity during prasugrel treatment as well. Ticagrelor is metabolized mainly by CYP3A4, which does not show functionally relevant genetic variability. Its concentrations may be modified by the variants of Pglycoprotein gene ABCB1. While no substantial difference between the clinical efficacy of prasugrel and ticagrelor has been documented, both of them have been shown to be superior to clopidogrel in post-ACS treatment. This can be partially explained by lower variability at each step of their metabolism. It is probable that factors influencing the pharmacokinetics of both drugs, including genetic factors, may predict the clinical efficacy of antiplatelet treatment in personalized medicine. CONCLUSION: We summarize the pharmacokinetics and pharmacogenetics of P2Y12 inhibitors with respect to their clinical effects in post-myocardial infarction treatment.

• MeSH
• antagonisté purinergních receptorů P2Y škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• biotransformace genetika   MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• cytochrom P450 CYP2C19 genetika   metabolismus   MeSH
• farmakogenomické varianty * MeSH
• infarkt myokardu krev   diagnóza   farmakoterapie   MeSH
• inhibitory agregace trombocytů škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• klopidogrel škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• léková rezistence genetika   MeSH
• lidé MeSH
• P-glykoproteiny genetika   metabolismus   MeSH
• prasugrel hydrochlorid škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• purinergní receptory P2Y12 krev   účinky léků   MeSH
• ticagrelor škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• trombocyty účinky léků   metabolismus   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• Publikační typ
• souhrny MeSH

BACKGROUND: Little is known about the effects of physical activity and fitness on sleep timing parameters in adolescence. METHODS: We investigated the development of sleep timing between age 8 and 15 and its association with physical fitness at age 15 in 787 adolescents (408 males, 379 females). Physical fitness was measured using the physical work capacity (PWC) protocol. Information on sport activity was collected at ages 11 and 15. Finally, the contribution of other covariates (sex, body mass index (BMI), parental education and occupational skill level) to the association between sleep parameters and physical fitness was evaluated. The correlation of BMI and physical fitness was assessed separately. RESULTS: Mild correlation of sleep duration at ages 8 and 15 was observed (r=0.08-0.16). Higher sport activity participation and physical fitness were found to be mildly associated with delayed bedtime and reduced sleep duration; the association with bedtime was significant after adjustment for all covariates. Sport activity at age 11 was not associated with sleep timing at age 15. Interestingly, higher BMI was linked to delayed bedtime and higher physical fitness. CONCLUSION: Our findings do not support existing hypotheses suggesting the association of low physical activity and fitness with shorter sleep duration and high BMI in a generally non-obese adolescent population without severe sleep restriction.

• MeSH
• chování mladistvých * MeSH
• cvičení * MeSH
• dítě MeSH
• index tělesné hmotnosti * MeSH
• lidé MeSH
• longitudinální studie MeSH
• mladiství MeSH
• prospektivní studie MeSH
• spánek * MeSH
• zvyky * MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

Angiotensinogen (AGT), its active fragments and microRNA-31 (miR-31) play an important role in adipocyte differentiation. AGT contains a miR-31 polymorphic binding site. We hypothesize that the rs7079 polymorphism in the miR-31/584 binding site of the AGT gene could influence body fat distribution. A total of 751 subjects (195 men, 556 women) were enrolled in the study. The rs7079 genotypes were determined by qRT-PCR. Anthropometric measurements were taken on all subjects, who were subsequently divided into two groups: obese (>30 kg m(-2)) and non-obese (<30 kg m(-2)). Linear regression models were created to determine the contributions of sex, obesity status and rs7079 to all measured parameters. Adding the rs7079 genotype significantly contributed to the linear regression model for waist circumference (p = 0.013), hip circumference (p = 0.018) and supraspinal skin-fold thickness (p = 1 × 10(-3)). Differences between sexes and between the obese and non-obese groups were observed. Waist circumference was lower in men carrying the A allele (p = 0.022); hip circumference was higher only in obese women carrying the A allele (p = 0.015). While men carrying the A allele had lower supraspinal skin-fold thickness (p = 0.022), this parameter was found to be higher in A allele carrying women (p = 3 × 10(-3)). The higher total sum of skin-fold thickness in A allele carrying women was restricted to obese individuals (p = 0.028). The presence of the A allele was associated with both lower tricipital skin-fold thickness in non-obese women (p = 0.023) and a trend of higher thickness in non-obese men (p = 0.065). Significant associations of rs7079 in the AGT gene and body fat distribution were observed. The distribution followed opposing patterns in both sexes.

• Publikační typ
• časopisecké články MeSH

Genetic and non-genetic predictors of 15-year survival in patients with chronic three-vessel disease (3VD) were investigated. Coronary angiography was performed on 810 subjects with symptoms of stable ischemic heart disease in 1998. The patients with 3VD were genotyped for 23 candidate polymorphisms covering the PPAR-RXR pathway, matrix metalloproteinase-2, renin-angiotensin-aldosterone system, endothelin-1, cytokine genes, MTHFR and APO E variants. Fifteen-year survival data were obtained from the national insurance registry. All data were available in the case of 150 patients with 3VD. Statistical analysis used stepwise Cox regression with dominant, recessive, or additive mode of genetic expression. Involved variables included age, sex, BMI, blood pressure, diabetes, ejection fraction, left main stenosis, previously diagnosed coronary stenosis, myocardial infarction in personal history, and coronary bypass along with polymorphisms pre-selected by log-rank tests. Out of the 23 polymorphisms, four were included in the model construction. SNP in the IL-6 gene rs1800795 (-174 G/C) has been found to be a significant predictor of survival. This SNP was in a linkage disequilibrium with rs1800797 (-597 G/A) in the same gene (D'=1.0), which was also found to constitute a significant predictor of survival when rs1800795 was not included in the model construction. Age, increased BMI, diabetes, low EF, and left main stenosis were also significant predictors in all models. Age, increased BMI, diabetes, low ejection fraction, left main stenosis, and genetic variation in the IL-6 promoter were established as significant independent risk factors for the survival of patients with three-vessel disease.

• MeSH
• DNA genetika   MeSH
• genetická predispozice k nemoci * MeSH
• interleukin-6 krev   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• nemoci koronárních tepen genetika   mortalita   radiografie   MeSH
• polymerázová řetězová reakce MeSH
• polymorfismus genetický * MeSH
• předpověď * MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• registrace * MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

AIMS: The impact of ApoE polymorphism on angiographic parameters was assessed in patients referred for coronary angiography. METHODS: Elective coronary angiography was performed in 671 subjects (525 men, 146 women, mean age 60 ± 10 years) with symptoms of ischemic heart disease. The patients were divided into: no CAD group (smooth coronary vessels, n=83), one-vessel (n=155), two-vessel (n=170) and three-vessel disease (n=196). Patients with stenoses 0-50% were excluded. Within patients with CAD, we evaluated overall extent of CAD measured by the number of stenotic segments according to AHA (1 segment vs. 2-3 vs. ≥4), and the severity of the most serious stenosis (in percent). ApoE genotype was determined using real-time PCR. RESULTS: The frequency of ε2/ε3 genotype (n=56) was lower in the three-vessel disease group compared to one-vessel disease (OR=0.25, P=0.0019), two-vessel disease (OR=0.31, P=0.0114) or no CAD group (OR=0.24, P=0.0057). Frequency of ε2/ε3 decreased with the number of affected segments (1 vs. ≥4: OR=0.35, P=0.0143). The ε3/ε4+ε4/ε4 genotypes (n=123) were more frequent in CAD patients altogether compared with no CAD group (OR=2.30, P=0.019), while no impact of the ε4 allele on angiographic parameters within the CAD patients was detected. In ε2/ε3 carriers with CAD, lower LDL-cholesterol, total cholesterol and lower use of lipid-lowering drugs were observed. CONCLUSIONS: The results show predominantly focal form of CAD in patients with ε2/ε3 genotype. Lower LDL-cholesterol and total cholesterol may play the key role, although other contributing factors are discussed.

• MeSH
• apolipoproteiny E genetika   MeSH
• cholesterol krev   MeSH
• genotyp MeSH
• koronární angiografie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci koronárních tepen genetika   krev   radiografie   MeSH
• polymorfismus genetický MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH