In this open-label, laboratory-blinded, 2-way single dose study in 24 volunteers of both sexes we found that (1) nabumetone reaches mean Cmax ± SD of 0.56 ± 0.20 mg·L at mean tmax of 8.63 ± 7.05 hours, and mean area under the curve (AUC)last of 18.07 ± 7.19 h·mg·L; (2) there are no statistically significant differences between both sexes in pharmacokinetics of nabumetone; (3) 6-methoxy-2-naphthylacetic acid (6-MNA) reaches higher AUClast in men compared with women (mean ± SD, 721.23 ± 185.53 h·mg·L and 545.27 ± 97.69 h·mg·L, respectively; P = 0.013); (4) there is lower 6-MNA clearance in men (0.65 ± 0.22 L·h) in comparison with women (0.88 ± 0.18 L·h, P = 0.019), (5) intersubject variability of nabumetone and 6-MNA is between 35%-45% and 10%-30% for all assessed pharmacokinetics parameters (AUClast, Cmax, partial AUC values); (6) intrasubject variability (ISCV) for AUClast is low, 15.59% and 6.40% for nabumetone and 6-MNA, respectively, (7) ISCV for Cmax is 13.66% and 5.42% for nabumetone and 6-MNA, respectively. Nabumetone thus belongs to compounds with low to moderate ISCV and therefore this product is expected to produce consistent effects in clinical practice.
- MeSH
- butanony aplikace a dávkování farmakokinetika MeSH
- dospělí MeSH
- inhibitory cyklooxygenasy 2 aplikace a dávkování farmakokinetika MeSH
- kyseliny naftalenoctové farmakokinetika MeSH
- lidé MeSH
- mladý dospělý MeSH
- plocha pod křivkou MeSH
- sexuální faktory MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
Cílem bylo provést interakční studie substrátů a silných inhibitorů enzymu CYP3A4 z hlediska dynamiky jejich vzájemného ovlivnění, tj. ve vztahu ke známým farmakokinetickým datům. Výsledky těchto interakčních studií pak vyhodnotit zejména z hlediska délky interakce, wash-out periody a predikce optimálního dávkování. Všechny interakční studie byly provedeny v programu pro kompartmentové modelování farmakokinetiky a farmakodynamiky Edsim++. Potřebná data pro tvorbu kompartmentových modelů byla získána z již provedených in vitro interakčních experimentů. Pro vyhodnocení dat pak byly využity časové průběhy plasmatických koncentrací léčiv, plochy pod koncentrační křivkou léčiv AUC před a po interakci s inhibitorem a maximální dosažené plasmatické koncentrace Cmax. V programu Edsim++ byly vytvořeny interakční modely substrátů CYP3A4 se silnými inhibitory tohoto enzymu: midazolam-ketokonazol (MK), midazolam- -itrakonazol (MI), midazolam-ritonavir (MR). Délka trvání interakce činila 150 h (MK), 216 h (MI), 246 h (MR). Plocha pod koncentrační křivkou substrátů AUC byla zvýšena o 545 % (MK), 291 % (MI), 537 % (MR). Maximální dosažené koncentrace substrátů Cmax byly zvýšeny o 400 % (MK), 153 % (MI), 516 % (MR). Současné podání silných inhibitorů a substrátů CYP3A4 je kontraindikováno. Délka wash-out periody vychází z délky trvání interakce. Po podání ketokonazolu, itrakonazolu a ritonaviru by wash-out perioda měla být minimálně 7, 10 a 4 dny, než bude podáno jiné léčivo, které je substrátem enzymu CYP3A4.
Patients with ephedrone parkinsonism (EP) show a complex, rapidly progressive, irreversible, and levodopa non-responsive parkinsonian and dystonic syndrome due to manganese intoxication. Eye movements may help to differentiate parkinsonian syndromes providing insights into which brain networks are affected in the underlying disease, but they have never been systematically studied in EP. Horizontal and vertical eye movements were recorded in 28 EP and compared to 21 Parkinson's disease (PD) patients, and 27 age- and gender-matched healthy subjects using standardized oculomotor tasks with infrared videooculography. EP patients showed slow and hypometric horizontal saccades, an increased occurrence of square wave jerks, long latencies of vertical antisaccades, a high error rate in the horizontal antisaccade task, and made more errors than controls when pro- and antisaccades were mixed. Based on oculomotor performance, a direct differentiation between EP and PD was possible only by the velocity of horizontal saccades. All remaining metrics were similar between both patient groups. EP patients present extensive oculomotor disturbances probably due to manganese-induced damage to the basal ganglia, reflecting their role in oculomotor system.
- MeSH
- bazální ganglia patofyziologie MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mangan toxicita MeSH
- mozek patofyziologie MeSH
- parkinsonské poruchy chemicky indukované patofyziologie MeSH
- pohyby očí fyziologie MeSH
- poruchy spojené s užíváním psychoaktivních látek patofyziologie MeSH
- propiofenony škodlivé účinky MeSH
- sakadické oční pohyby fyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Several candidate genes have been proposed as potential biomarkers for altered pharmacodynamics or pharmacokinetics of immunosuppressive drugs. However, there is usually only limited clinical evidence substantiating the implementation of biomarkers into clinical practice. Testing for thiopurine-S-methyltransferase polymorphisms has been put into routine clinical use quite widely, while the other pharmacogenetic tests are much less frequently used. Relatively good evidence appeared for tacrolimus-related biomarkers; thus, their utilization may be envisaged in the near future. Although the biomarkers related to mycophenolate, sirolimus or other drugs in the therapeutic class may be promising, further research is necessary to provide more robust evidence. The present review focuses on immunosuppressive drugs, excluding biological treatment.
- MeSH
- farmakogenetika metody MeSH
- genetické markery * MeSH
- imunosupresiva farmakokinetika farmakologie MeSH
- lidé MeSH
- methyltransferasy genetika MeSH
- polymorfismus genetický MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The aim of prospective study was to evaluate the pain relief in the postoperative period and consumption of opioid and non-opioid analgesics as a risk factor of the anastomotic insufficiency after rectal and rectosigmoideal resection for carcinoma. Anastomotic insufficiency is one of the most feared and life threatening early complications. No articles about the effect of the response to opioid therapy in the postoperative period on the risk of this major clinical problem have been published. We compared the effect of opioid and non-opioid analgesics in 109 patients who underwent rectal and rectosigmoideal resection in a prospective study. We evaluated the appearance of anastomotic insufficiency and clinical conditions in the relationship with the pain relief in the postoperative period and consumption of opioid and non-opioid analgesics. The pain intensity and the consumption of analgesics were significantly increased in the group of nonresponders. The rate of PONV (postoperative nausea and vomiting) in the responders and nonresponders groups was 69% and 78%, respectively. However, the differences did not reach significant level. Other clinical conditions were not significantly different between the both groups, too. The difference in the incidence of anastomotic insufficiency between both groups was highly significant, 6% cases of anastomotic insufficiency in the responders group and 19% in nonresponders group (χ2 = 7.73; p=0.0054). Nonrespoders to opioid therapy and their high consumption of second-line analgesics is a high risk factor for anastomotic insufficiency.
- MeSH
- adenokarcinom chirurgie MeSH
- analgetika terapeutické užití MeSH
- anastomóza chirurgická MeSH
- incidence MeSH
- kolektomie metody MeSH
- kolon chirurgie MeSH
- lidé středního věku MeSH
- lidé MeSH
- management bolesti metody MeSH
- měření bolesti MeSH
- nádory rekta chirurgie MeSH
- nádory sigmoidea chirurgie MeSH
- následné studie MeSH
- netěsnost anastomózy epidemiologie prevence a kontrola MeSH
- pooperační bolest diagnóza farmakoterapie MeSH
- prospektivní 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
- multicentrická studie MeSH
- srovnávací studie MeSH
- Geografické názvy
- Česká republika MeSH
- Klíčová slova
- farmakogenomika, interindividuální variabilita,
- MeSH
- epoxidreduktasy vitaminu K farmakologie genetika účinky léků MeSH
- farmakogenetika * metody trendy MeSH
- genetické testování využití MeSH
- individualizovaná medicína * metody trendy MeSH
- lidé MeSH
- methyltransferasy farmakologie genetika MeSH
- nežádoucí účinky léčiv prevence a kontrola MeSH
- polymorfismus genetický fyziologie MeSH
- systém (enzymů) cytochromů P-450 farmakologie genetika MeSH
- transportní proteiny farmakologie MeSH
- určení vhodnosti pacienta metody MeSH
- Check Tag
- lidé MeSH
This paper reviews the impact of genetic variability of drug metabolizing enzymes, transporters, receptors, and pathways involved in chronic pain perception on the efficacy and safety of analgesics and other drugs used for chronic pain treatment. Several candidate genes have been identified in the literature, while there is usually only limited clinical evidence substantiating for the penetration of the testing for these candidate biomarkers into the clinical practice. Further, the pain-perception regulation and modulation are still not fully understood, and thus more complex knowledge of genetic and epigenetic background for analgesia will be needed prior to the clinical use of the candidate genetic biomarkers.
- MeSH
- biologické markery krev MeSH
- chronická bolest krev genetika MeSH
- cytokiny metabolismus MeSH
- farmakogenetika metody MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
AIM: CYP2C8 represents 7% of the hepatic cytochrome system and metabolizes around 5% of drugs in phase I processes. It also plays a significant role in metabolism of endogenous compounds. More than 20 single-nucleotide polymorphisms (SNPs) have been noted, mainly in exons 3, 5, and 8. The most studied SNPs may lead to decreased enzyme activity and may have impact on drug metabolism. Variant alleles are called CYP2C8*2 (I269F), CYP2C8*3 (R139K, K399R), and CYP2C8*4(I264M). Our aim was to investigate the frequency of major functional SNPs among the Czech population. MATERIAL AND METHODS: DNA was isolated from whole blood of 161 healthy, young, and unrelated subjects (94 men and 67 women, aged from 23 to 28 years). The genotypes of polymorphic positions CYP2C8*2, CYP2C8*3 (G416A, A1196G), and CYP2C8*4 were determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS AND CONCLUSION: Observed allele frequencies were 10.9%, 5.9%, and 0.3% for the alleles CYP2C8*3, CYP2C8*4, and CYP2C8*2, respectively. Both CYP2C8*3 (G416A, A1196G) alleles have been found in complete linkage disequilibrium. The allele distribution complies well with Hardy-Weinberg equilibrium. Allele frequencies of functionally important CYP2C8 variants in the Czech population are similar to that of other Caucasian populations.
- MeSH
- alely MeSH
- aromatické hydroxylasy genetika metabolismus MeSH
- dospělí MeSH
- exony genetika MeSH
- frekvence genu MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- polymorfismus délky restrikčních fragmentů MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Geografické názvy
- Česká republika MeSH
Cílem práce bylo zavést a validovat analytickou metodu, která by umožnila detekovat koncentrace nabumetonu a kyseliny 6-methoxy-2-naftyloctové (6-MNA) po jednorázovém podání terapeutické dávky léčiva. Byly porovnány dvě metody stanovení pomocí HPLC s UV a hmotnostní detekcí. Při úpravě vzorku bylo optimálních výsledků dosaženo pomocí extrakce na pevné fázi (SPE). Výtěžnost se pohybovala okolo 84 % pro nabumeton a 86–90 % pro 6-MNA. HPLC separace analytů byla prováděna na reverzní C18 koloně. Limit UV detekce pro 6-MNA byl 50 nM, pro nabumeton 0,1 µM. Limit MS detekce pro 6-MNA činil 1 µM, pro nabumeton 0,5 µM. Přesnost metody pro stanovení nabumetonu se pohybovala v rozmezí 4,2–14,4 % při UV detekci a 4,6–8,5 % při MS detekci. Přesnost metody pro 6-MNA byla 2,4–12,5% při UV detekci a 2,1–9,4 % při MS detekci. Správnost metody pro stanovení nabumetonu se pohybovala v rozmezí 93,4–109,6 % při UV detekci a 86,2–107,9 % při MS detekci. Správnost metody pro 6-MNA byla 87,8–107,4 % při UV detekci a 86,3–106,4 % při MS detekci. Vhodnost metody byla ověřená na vzorcích pro stanovení farmakokinetiky léčiva u 24 zdravých dobrovolníků.
The study aimed to establish and validate an analytical method for the determination of nabumetone and 6-methoxy-2-naphthylacetic acid (6-MNA) in human plasma after a single therapeutic dose of the drug. Two methods based on HPLC with UV and MS detection were compared. Optimal results in sample preparation were achieved using solid phase extraction. The recovery reached approximately 84% and 86–90% for nabumetone and 6-MNA, respectively. A reverse C18 column was used for HPLC separation of the analytes. The limit of UV detection was 50 nM and 0.1 µM for 6-MNA and nabumetone, respectively. The limit of MS detection was 1 µM and 0.5 µM for 6-MNA and nabumetone, respectively. Precision ranged between 4.2–14.4% and 4.6–8.5% using UV and MS detection for nabumetone, respectively. The respective values for 6-MNA were 2.4–12.5% and 2.1–9.4%. Accuracy ranged between 93.4–109.6% in UV detection and 86.2–107.9% using UV and MS detection for nabumetone, respectively. The respective values for 6-MNA were 87.8–107.4% and 86.3–106.4%. The method was subsequently applied to determine the pharmacokinetic parameters of nabumetone and 6-MNA in a group of 24 healthy volunteers.
A rapid and sensitive method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for enantiomeric determination of tramadol and its primary phase metabolite O-desmethyltramadol in human plasma has been developed. Tramadol hydrochloride-(13)C, d(3), was used as an isotopic labeled internal standard for quantification. The method involves a simple solid phase extraction. The analytes and internal standard were separated on Lux Cellulose-2 packed with cellulose tris(3-chloro-4-methylphenylcarbamate) using isocratic elution with hexane/isopropanol/diethylamine (90:10:0.1, v/v/v) at a flow rate of 1.3 mL/min. The APCI positive ionization mass spectrometry was used with multiple reaction monitoring of the transitions at m/z 264.2-->58.2 for tramadol, m/z 250.1-->58.2 for O-desmethyltramadol and m/z 268.2-->58.2 for internal standard. Linearity was achieved between 1-800 ng/mL and 1-400 ng/mL (R(2) > or = 0.999) for each enantiomer of tramadol and O-desmethyltramadol, respectively. Intra-day accuracies ranged among 98.2-102.8%, 97.1-109.1% and 97.4-102.9% at the lower, intermediate, and high concentration for all analytes, respectively. Inter-day accuracies ranged among 95.5-104.1%, 99.2-104.7%, and 94.2-105.6% at the lower, intermediate, and high concentration for all analytes, respectively. This assay was successfully used to determine the concentration of enantiomers of tramadol and O-desmethyltramadol in a pharmacogenetic study.
- MeSH
- časové faktory MeSH
- chromatografie kapalinová metody MeSH
- cytochrom P-450 CYP2D6 genetika MeSH
- extrakce na pevné fázi MeSH
- fenotyp MeSH
- hmotnostní spektrometrie metody MeSH
- kalibrace MeSH
- lidé MeSH
- limita detekce MeSH
- reprodukovatelnost výsledků MeSH
- stereoizomerie MeSH
- tramadol analogy a deriváty krev chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
