BACKGROUND: Therapeutic drug monitoring (TDM) can identify patients with subtherapeutic asparaginase (ASNase) activity [silent inactivation (SI)] and prospectively guide therapeutic adaptation. However, limited intra-individual variability is a precondition for targeted dosing and the diagnosis of SI. METHODS: In the AIEOP-BFM acute lymphoblastic leukemia (ALL) 2009 trial, 2771 children with ALL were included and underwent ASNase-TDM in a central laboratory in Münster. Two biweekly administrations of pegylated ASNase during induction and a third dose during reinduction or the high-risk block, which was administered several weeks later, were monitored. We calculated (1) the incidence of SI; and (2) the predictivity of SI for SI after the subsequent administration. ASNase activities monitored during induction were categorized into percentiles at the respective sampling time points. These percentiles were used to calculate the intra-individual range of percentiles as a surrogate for intrapatient variability and to evaluate the predictivity of ASNase activity for the subsequent administration. RESULTS: The overall incidence of SI was low (4.9%). The positive predictive value of SI identified by one sample was ≤21%. Confirmation of SI by a second sample indicated a high positive predictive value of 100% for biweekly administrations, but not for administration more than 17 weeks later. Sampling and/or documentation errors were risks for misdiagnosis of SI. High intra-individual variability in ASNase activities, with ranges of percentiles over more than 2 quartiles and low predictivity, was observed in approximately 25% of the patients. These patients were likely to fail dose individualization based on TDM data. CONCLUSIONS: To use TDM as a basis for clinical decisions, standardized clinical procedures are required and high intra-individual variability should be taken into account. Details of the treatment are available in the European Clinical Trials Database at https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004270-43/DE.
- MeSH
- akutní lymfatická leukemie farmakoterapie MeSH
- asparagin krev MeSH
- asparaginasa aplikace a dávkování krev terapeutické užití MeSH
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- metabolická inaktivace fyziologie MeSH
- mladiství MeSH
- monitorování léčiv metody MeSH
- polyethylenglykoly aplikace a dávkování terapeutické užití MeSH
- předškolní dítě MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The understanding of drug biotransformation is an important medical topic. The oxidative pathways that involve CYPs have been extensively studied in drug metabolism in contrast to the reductive pathways. This review focuses on drugs that have been reported to be reduced at the carbonyl group in vivo. Although the carbonyl reduction of these drugs is well known, our understanding of the carbonyl reducing enzymes (CRE) that perform these reactions is limited. We have summarized the published data in order to thoroughly describe the reductive metabolism of the selected drugs and to demonstrate the role of carbonyl reduction in the context of their overall metabolism. The number of drugs recognized as substrates for CREs has increased considerably in recent years. Moreover, the importance of carbonyl reduction in the overall metabolism of these drugs is often surprisingly high. Because only limited information is available about the CREs responsible for these reactions, additional research is needed to improve our understanding of the metabolism of drugs undergoing carbonyl reduction. Carbonyl reduction should be investigated during drug development because it can either positively or negatively influence drug efficacy.
- MeSH
- akupunkturní dráhy * MeSH
- fyziologie výživy kojenců fyziologie MeSH
- fyziologie výživy * fyziologie MeSH
- holistické zdraví MeSH
- kojenec MeSH
- lidé MeSH
- maso škodlivé účinky MeSH
- metabolická inaktivace fyziologie MeSH
- omezení příjmu potravy MeSH
- ořechy metabolismus škodlivé účinky MeSH
- ovoce metabolismus škodlivé účinky MeSH
- pankreas * MeSH
- potravinová alergie MeSH
- potraviny klasifikace MeSH
- preference v jídle MeSH
- přijímání potravy fyziologie psychologie MeSH
- rýže (rod) metabolismus škodlivé účinky MeSH
- sacharidy škodlivé účinky MeSH
- slezina * MeSH
- stravovací zvyklosti MeSH
- tradiční čínská medicína MeSH
- tuky škodlivé účinky MeSH
- žaludek * MeSH
- zdravé chování MeSH
- zelenina metabolismus škodlivé účinky MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
Nespavost u seniorů je stále závažným problémem klinické praxe. Zatímco pro krátkodobou terapii nespavosti lze použít řadu preparátů, pro terapii chronické nespavosti se stále hledá optimální léčebný postup. Žádné z dosud užívaných hypnotik pro terapii chronické nespavosti není u seniorů bez rizika. Poslední data ukazují na riziko vzniku závislosti i odvykacích stavů při dlouhodobé léčbě chronické nespavosti u seniorů pomocí Z-látek (zolpidem, zopiklon, zaleplon). Závěrem přehledové práce je přinesena kazuistika pacientky, která byla přijata na gerontopsychiatrické oddělení Psychiatrické nemocnice v Kroměříži pro závislost na zolpidemu. U této pacientky byla postupně redukována dávka zolpidemu za přispění dočasně užívaného klonazepamu, zolpidem se nakonec podařilo zcela vysadit a nahradit melperonem, placebem a psychoterapeutickým vedením.
Insomnia in seniors remains a serious problem in clinical practice up to now. Meanwhile insomnia in short-term treatment strategy can be treated with various substances, long-term treatment strategy of chronic insomnia is still searching optimal management. None of drugs for long-term treatment of insomnia in seniors stays without any risk. Latest data about chronic insomnia treatment with Z-agents (zolpidem, zopiclone, zaleplone) refer about increased risk of dependency as well as withdrawal states especially when Z-agents are used for a long time. At the end of review a case report of a patient addicted to zolpidem and admitted to psychogeriatric ward in Mental hospital Kroměříž is reported. In this case dose of zolpidem was gradually decreased, thanks to initial contribution of melperone. Finally, the use of zolpidem was completely stopped in our patient and replaced by melperone, placebo and psychotherapy.
- MeSH
- duševní poruchy farmakoterapie chemicky indukované psychologie MeSH
- hypnotika a sedativa farmakologie kontraindikace škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- metabolická inaktivace fyziologie MeSH
- placeba terapeutické užití MeSH
- poruchy iniciace a udržování spánku * diagnóza farmakoterapie MeSH
- předávkování léky * diagnóza farmakoterapie psychologie MeSH
- psychoterapie metody MeSH
- pyridiny * aplikace a dávkování farmakokinetika farmakologie škodlivé účinky terapeutické užití MeSH
- senioři MeSH
- věkové faktory MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- přehledy MeSH
Process of aging is accompanied by changes in the biotransformation of xenobiotics and impairment of normal cellular functions by free radicals. Therefore, this study was designed to determine age-related differences in the activities and/or expressions of selected drug-metabolizing and antioxidant enzymes in young and old rats. Specific activities of 8 drug-metabolizing enzymes and 4 antioxidant enzymes were assessed in hepatic subcellular fractions of 6-week-old and 21-month-old male Wistar rats. Protein expressions of carbonyl reductase 1 (CBR1) and glutathione S-transferase (GST) were determined using immunoblotting. Remarkable age-related decrease in specific activities of CYP2B, CYP3A, and UDP-glucuronosyl transferase was observed, whereas no changes in activities of CYP1A2, flavine monooxygenase, aldo-keto reductase 1C, and antioxidant enzymes with advancing age were found. On the other hand, specific activity of CBR1 and GST was 2.4 folds and 5.6 folds higher in the senescent rats compared with the young ones, respectively. Interindividual variability in CBR1 activity increased significantly with rising age. We suppose that elevated activities of GST and CBR1 may protect senescent rats against xenobiotic as well as eobiotic electrophiles and reactive carbonyls, but they may alter metabolism of drugs, which are CBR1 and especially GSTs substrates.
- MeSH
- aktivace enzymů MeSH
- antioxidancia metabolismus MeSH
- játra enzymologie MeSH
- krysa rodu rattus MeSH
- léčivé přípravky MeSH
- metabolická clearance MeSH
- metabolická inaktivace fyziologie MeSH
- oxidoreduktasy MeSH
- potkani Wistar MeSH
- stárnutí metabolismus MeSH
- xenobiotika farmakokinetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVES: The aim of this study was to compare the acute toxicity of acetylsalicylic acid to embryonic and juvenile stages of aquarium fish - zebrafish (Danio rerio), oxidative stress parameters and detoxifying enzyme. METHODS: Tests were performed according to OECD No. 203 (Fish, acute toxicity test) and OECD No. 212 (Fish, short-term toxicity test on embryo and sac-fry stages) methodology. RESULTS: The results showed the mean acetylsalicylic acid LC50 value to be 567.7 mg/L in juvenile zebrafish. The acute toxicity of acetylsalicylic acid for zebrafish embryos was 274.6 mg/L. Statistically significantly higher activity of GST was found in concentrations 340, 380 and 420 mg/L of acetylsalicylic acid. TBARS, GPx and GST didn't show statistically significant activity in tested concentrations of acetylsalicylic acid. CONCLUSIONS: The results revealed a statistically significantly higher degree of sensitivity in the embryonic stages of zebrafish compared to its juveniles. Acetylsalicylic acid did not cause statistically significantly higher antioxidative defence in zebrafish.
- MeSH
- antiflogistika nesteroidní toxicita MeSH
- Aspirin toxicita MeSH
- chemické látky znečišťující vodu toxicita MeSH
- dánio pruhované embryologie MeSH
- embryo nesavčí účinky léků MeSH
- kvalita vody MeSH
- LD50 MeSH
- metabolická inaktivace fyziologie MeSH
- oxidační stres účinky léků fyziologie MeSH
- testy akutní toxicity MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: 2-Nitrobenzanthrone (2-NBA) has recently been detected in ambient air particulate matter. Its isomer 3-nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust. Understanding which enzymes are involved in metabolism of these toxicants is important in the assessment of individual susceptibility. Here, metabolism of 2-NBA and 3-NBA by rat and mouse hepatic microsomes containing cytochromes P450 (CYPs), their reductase (NADPH:CYP reductase), and NADH:cytochrome b5 reductase was investigated under anaerobic and aerobic conditions. In addition, using the same microsomal systems, 2-NBA and 3-NBA were evaluated to be enzymatically activated under anaerobic conditions to species generating 2-NBA- and 3-NBA-derived DNA adducts. METHODS: High performance liquid chromatography (HPLC) with ultraviolet (UV) detection was employed for the separation and characterization of 2-NBA and 3-NBA metabolites formed by hepatic microsomes of rats and mice under the anaerobic and aerobic conditions. Microsomal systems isolated from the liver of the control (untreated) rats and rats pretreated with Sudan I, β-naphthoflavone (β-NF), phenobarbital (PB), ethanol and pregnenolon 16α-carbonitrile (PCN), the inducers of cytochromes P450 (CYP) 1A1, 1A1/2, 2B, 2E1 and 3A, respectively, were used in this study. Microsomes of mouse models, a control mouse line (wild-type, WT) and Hepatic Cytochrome P450 Reductase Null (HRN) mice with deleted gene of NADPH:CYP reductase in the liver, thus absenting this enzyme in their livers, were also employed. To detect and quantify the 2-NBA- and 3-NBA-derived DNA adducts, the 32P postlabeling technique was used. RESULTS: Both reductive metabolite of 3-NBA, 3-aminobenzanthrone (3-ABA), found to be formed predominantly under the anaerobic conditions, and two 3-NBA oxidative metabolites, whose structures have not yet been investigated, were formed by several microsomal systems used in the study. Whereas a 3-NBA reductive metabolite, 3-ABA, was found only in the microsomal systems of control rats, the rats treated with β-NF and PB, and microsomes of WT and HRN mice, all hepatic microsomes tested in the study were capable of activating this carcinogen under the reductive conditions to form DNA adducts. A stability of a reactive intermediate of 3-NBA, N-hydroxy-3-aminobenzanthrone that is formed during 3-NBA reduction to 3-ABA, to form nitrenium (and/or carbenium) ions binding to DNA in individual microsomes as well as binding of these ions to proteins of these microsomes, might be the reasons explaining this phenomenon. In contrast to 3-NBA, its isomer 2-NBA was not metabolized by any of the used enzymatic systems both under the anaerobic and aerobic conditions. Likewise, no DNA adducts were detectable after reaction of 2-NBA in these systems with DNA. CONCLUSIONS: The results found in this study, the first report on the metabolism of 2-NBA and 3-NBA by rat and mouse hepatic microsomes demonstrate that 3-NBA, in contrast to 2-NBA, is reductively activated to form 3-NBA-derived DNA adducts by these enzymatic systems. NADPH:CYP reductase can be responsible for formation of these DNA adducts in rat livers, while NADH:cytochrome b5 reductase can contribute to this process in livers of HRN mice.
- MeSH
- adukty DNA metabolismus MeSH
- aerobióza fyziologie MeSH
- anaerobióza fyziologie MeSH
- benz(a)anthraceny farmakokinetika toxicita MeSH
- cytochrom-B(5)-reduktasa genetika metabolismus MeSH
- inbrední kmeny myší MeSH
- jaterní mikrozomy enzymologie MeSH
- karcinogeny farmakokinetika toxicita MeSH
- krysa rodu rattus MeSH
- látky znečišťující vzduch farmakokinetika toxicita MeSH
- metabolická inaktivace fyziologie MeSH
- modely u zvířat MeSH
- myši knockoutované MeSH
- myši MeSH
- NADPH-cytochrom c-reduktasa metabolismus MeSH
- potkani Wistar MeSH
- substrátová specifita fyziologie MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- výfukové emise vozidel toxicita MeSH
- zdraví ve městech MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Demografické trendy v rozvinutých zemích přinášejí nové výzvy. Jednou z nich je léčba psychiatrických onemocnění u seniorské populace. Kvůli farmakokinetickým a farmakodynamickým změnám, které přicházejí s věkem, má použití psychofarmak u starší a nejstarší populace svá často přehlížená specifika. Potýkáme se nejenom s řadou nežádoucích účinků, které jsou s věkem akcentovány, ale i s otazníky nad účinností těchto léčiv, poměrem mezi riziky a přínosy a složitými interakcemi s dalšími medikamenty. Článek mapuje úskalí použití psychofarmak u starší populace psychiatricky nemocných jedinců.
Current demographic trends in the industrial world bring new challenges. One of them is treatment of psychiatric disorders in senior citizens. Due to pharmacokinetic and pharmacodynamic changes brought about by age, usage of psychopharmaceuticals in old to very old patients has its specifics that are often overlooked. We have to deal not only with a range of adverse effects, which are accentuated by advanced age, but also with questions about efficacy of these drugs, the ratios between risks and benefits and intricate interactions with other drugs. The article tries to map the pitfalls of using psychopharmaceuticals in the elderly segment of psychiatric patients.
- Klíčová slova
- gerontopsychiatrie, geriatrická populace,
- MeSH
- antidepresiva farmakokinetika farmakologie terapeutické užití MeSH
- antipsychotika farmakokinetika farmakologie terapeutické užití MeSH
- geriatrická psychiatrie metody trendy MeSH
- hyponatremie komplikace MeSH
- lidé MeSH
- metabolická inaktivace fyziologie MeSH
- metabolismus fyziologie imunologie účinky léků MeSH
- nežádoucí účinky léčiv etiologie komplikace MeSH
- psychotropní léky farmakokinetika farmakologie terapeutické užití MeSH
- senioři MeSH
- stárnutí fyziologie metabolismus účinky léků MeSH
- statistika jako téma MeSH
- syndrom nepřiměřené sekrece ADH komplikace MeSH
- systém (enzymů) cytochromů P-450 metabolismus účinky léků MeSH
- věkové faktory MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
Lékovou interakci můžeme charakterizovat jako jev, kdy se plazmatická koncentrace, a tím i účinky původního léku změní, protože k léku přidáme lék jiný nebo dojde ke kombinaci s určitými druhy potravin. Význam lékových interakcí vzrůstá s polypragmazií. Interakce antipsychotik vznikají na úrovni farmakodynamické a farmakokinetické. Farmakokinetika studuje absorpci, distribuci, metabolismus a exkreci farmaka či jeho metabolitů v lidském těle. Farmakodynamika sleduje profil a intenzitu farmakologického působení daného léku. Z pohledu farmakodynamiky antipsychotika ovlivňují zejména dopaminové, serotoninové, adrenergní, muskarinové a histaminové receptory. Mezi farmakodynamické interakce rovněž patří epileptogenní působení antipsychotik, riziko prodloužení QTc intervalu, hematotoxicita či útlum centrální nervové soustavy. Farmakokinetické interakce antipsychotik spočívají v ovlivnění jejich absorpce, distribuce, metabolismu a exkrece. Nejdůležitější je fáze metabolizace zahrnující oxidaci, redukci a hydrolýzu antipsychotik. Nejvýznamnější je oxidace antipsychotik cytochromem P 450, pro interakce antipsychotik mají potom největší význam tři jeho izoenzymy 2D6, 1A2 a 3A4). Mezi základní znalosti psychiatrů by mělo patřit povědomí o receptorovém profilu a hlavní cesty metabolismu daného psychofarmaka.
Drug interaction can be defined as occurring when the concentration of one drug in the blood plasma (and therefore its effects) are modified either when another drug is added, or in combination with certain foodstuffs or other substances. The significance of drug interaction increases with polypharmacy. Antipsychotics can have interactions on pharmacokinetic level and on pharmacodynamic level. Pharmacokinetics studies absorption, distribution, metabolism and excretion of the drug or its metabolites in the human body. Pharmacodynamics studies the profile and intensity of the pharmacological effects of the given drug. From the point of view of pharmacodynamics, antipsychotics affect mainly the dopamine, serotonin, adrenergic, muscarine and histamine receptors. Other pharmacodynamical interactions include epileptogenic effects of antipsychotics, the risk of prolonging the QTc interval, hematotoxicity and inhibition of central nervous system. Pharmacokinetic interactions of antipsychotics consist in influences to their absorption, metabolism and excretion. The crucial phase is their metabolisation, including oxidation, reduction and hydrolysis of antipsychotics. Oxidation of antipsychotics by cytochrome P 450 is the most significant process there, and the isoenzymes 2D6, 1A2 and 3A4 have the most importance in regards to interaction of antipsychotics. For psychiatrists, awareness of the receptor profile and main metabolic pathways of the psychoactive drugs prescribed should be considered as one of the basic pieces of knowledge.
- Klíčová slova
- farmakodynamika, CYP450,
- MeSH
- adrenergní receptory metabolismus účinky léků MeSH
- antipsychotika farmakokinetika farmakologie škodlivé účinky MeSH
- farmakokinetika MeSH
- financování organizované MeSH
- hematopoetický systém metabolismus účinky léků MeSH
- interakce mezi potravou a léky MeSH
- kardiovaskulární systém metabolismus účinky léků MeSH
- lékové interakce MeSH
- lidé MeSH
- metabolická inaktivace fyziologie genetika imunologie MeSH
- nervový systém metabolismus účinky léků MeSH
- nežádoucí účinky léčiv MeSH
- polypharmacy MeSH
- receptory dopaminové metabolismus účinky léků MeSH
- receptory muskarinové metabolismus účinky léků MeSH
- systém (enzymů) cytochromů P-450 metabolismus účinky léků MeSH
- věkové faktory MeSH
- Check Tag
- lidé MeSH
