The objective of this prospective study was to examine the exposure to the main active metabolites of ciprofloxacin in critically ill patients and to examine the factors (demographic, laboratory and genetic) that could potentially affect the drug metabolic conversion of ciprofloxacin. The secondary aim was to develop a population pharmacokinetic model for the metabolite showing the most associations with the abovementioned factors. A total of 29 patients were treated with intravenous infusion of ciprofloxacin and enrolled on this trial. Blood samples for pharmacokinetic analysis were taken at 1, 4, and 11.5 h following the completion of the infusion. Sex, age, body weight, height, serum creatinine and bilirubin levels, and creatinine clearance (CLCR) were recorded, and polymorphisms rs2032582 and rs1045642 in the ABCB1 gene, rs4148977 in the SLCO1A2 gene and rs762551 in the CYP1A2 gene were analyzed. A three-stage parent drug-metabolite population pharmacokinetic model was developed. Median (IQR) metabolite/parent ratios of the desethylene ciprofloxacin, formyl ciprofloxacin and oxociprofloxacin were 5.86 (4.09-9.87)%, 4.08 (3.38-6.92)% and 5.91 (3.42-13.65)%, respectively. The desethylene ciprofloxacin metabolic ratio was positively associated with height (r2 = 0.2277, p = 0.0089) and CLCR (r2 = 0.2023, p = 0.0144) and negatively associated with age (r2 = 0.2227, p = 0.0112). Males had a significantly higher oxociprofloxacin metabolic ratio than females (9.14 vs 3.42%, p = 0.0043). In the desethylene ciprofloxacin population PK model, the volume of distribution decreased with age, the parent drug-metabolite transfer rate constant increased with CLCR, and the metabolite elimination rate constant decreased with age and is increased in CYP1A2 rs762551 variant allele carriers. We therefore hypothesized that the CYP1A2 inhibition by ciprofloxacin is mediated by its metabolite desethylene ciprofloxacin.

• Publikační typ
• časopisecké články MeSH

Anastrozole is a selective non-steroidal aromatase inhibitor that blocks the conversion of androgens to estrogens in peripheral tissues. It is used as adjuvant therapy for early-stage hormone-sensitive breast cancer in postmenopausal women. Significant side effects of anastrozole include osteoporosis and increased levels of cholesterol. To date, seven case reports on anastrozole hepatotoxicity have been published. We report the case of an 81-year-old woman with a history of breast cancer, arterial hypertension, type 2 diabetes mellitus, hyperlipidemia, and chronic renal insufficiency. Four days after switching hormone therapy from tamoxifen to anastrozole, icterus developed along with a significant increase in liver enzymes (measured in the blood). The patient was admitted to hospital, where a differential diagnosis of jaundice was made and anastrozole was withdrawn. Subsequently, hepatic functions quickly normalized. The observed liver injury was attributed to anastrozole since other possible causes of jaundice were excluded. However, concomitant pharmacotherapy could have contributed to the development of jaundice and hepatotoxicity, after switching from tamoxifen to anastrozole since several the patient's medications were capable of inhibiting hepatobiliary transport of bilirubin, bile acids, and metabolized drugs through inhibition of ATP-binding cassette proteins. Telmisartan, tamoxifen, and metformin all block bile salt efflux pumps. The efflux function of multidrug resistance protein 2 is known to be reduced by telmisartan and tamoxifen and breast cancer resistance protein is known to be inhibited by telmisartan and amlodipine. Moreover, the activity of P-glycoprotein transporters are known to be decreased by telmisartan, amlodipine, gliquidone, as well as the previously administered tamoxifen. Finally, the role of genetic polymorphisms of cytochrome P450 enzymes and/or drug transporters cannot be ruled out since the patient was not tested for polymorphisms.

• Publikační typ
• kazuistiky MeSH

Východiska: Monoklonální imunoglobuliny (paraproteiny) jsou produkovány B lymfocyty při lymfoproliferativním onemocnění. Jsou charakteristické svou homogenní strukturou, v séru se mohou vyskytovat ve vysokých koncentracích a mohou být příčinou významné interference při laboratorních stanoveních. Případ: 84letý pacient byl hospitalizován na interním oddělení pro progresi dušnosti. V základním laboratorním vyšetření jsme zaznamenali vysoký konjugovaný bilirubin a nízký celkový bilirubin. Přímý sérový bilirubin byl měřen spektrofotometrickou metodou na principu diazoreakce. Důkladné došetření navzájem si odporujících výsledků vedlo k odhalení paraproteinu jako příčiny laboratorní interference, a tím k diagnostice maligního lymfoproliferativního onemocnění, které u pacienta do té doby nebylo známo. Závěr: Monoklonální imunoglobuliny jsou relativně vzácnou, ale o to klinicky závažnější, příčinou interference. Tato kazuistika ukazuje nutnost bdělého profesionálního přístupu při hodnocení laboratorních výsledků. Nečekaně vysoké, nízké či navzájem si odporující výsledky měření by měly vést ke zvážení přítomnosti monoklonálního imunoglobulinu a vyloučení jeho přítomnosti dalšími metodami (elektroforéza, imunofixace). Důsledkem těchto interferencí mohou být chyby v diagnostice a neadekvátní léčba. Na druhou stranu u pacientů, u nichž je známa přítomnost paraproteinu ve vyšších koncentracích, je nutno myslet na možné interference u rozličných biochemických stanovení a být obezřetný při poskytování péče opírající se o jejich hodnocení.

Background: Monoclonal immunoglobulins (paraproteins) are produced by B lymphocytes in lymphoproliferative disorders. A single monoclonal immunoglobulin is homogeneous in terms of its structure, and it can occur in human serum at high concentration and cause significant interference in laboratory assays. Case: We present a case of an 84-year-old man who was admitted to the hospital for progression of dyspnea. Basic laboratory tests showed a serum concentration of conjugated bilirubin, measured using the diazo spectrophotometric method, which was much higher than that of total bilirubin. The cause of the discrepancy was attributed to analytical interference by monoclonal immunoglobulins, which helped establish a diagnosis of lymphoproliferative disorder. Conclusion: Monoclonal immunoglobulins are relatively rare in serum but are an important cause of analytical interference. Monoclonal immunoglobulins should always be considered a source of interference when unexpectedly high, low, or contradictory data are encountered, and appropriate confirmatory tests (electrophoresis, imunofixation) should be performed in such circumstances. Failure to do so can result in errors in diagnosis and inadequate treatment. Conversely, when samples contain abnormal and especially high monoclonal immunoglobulin levels, the biochemical data should be carefully examined for any discrepancies, such as paraprotein interference, and the results should be taken into consideration in patient management.

• MeSH
• bilirubin analýza   MeSH
• biochemie metody   MeSH
• chybná diagnóza MeSH
• diferenciální diagnóza MeSH
• fatální výsledek MeSH
• gastroezofageální reflux MeSH
• imunologické faktory MeSH
• klinická chemie normy   MeSH
• léčivé přípravky MeSH
• lidé MeSH
• lymfoproliferativní nemoci * diagnóza   MeSH
• paraproteiny MeSH
• senioři nad 80 let MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• Publikační typ
• kazuistiky MeSH

OBJECTIVE: Quercetin, a plant flavonoid with potent antioxidant action, has been shown to be ameliorative against different types of liver insults, including D-Galactosamine/Lipopolysaccharide (D-GalN/LPS). The notion that its cytoprotective effects are SIRT1 mediated is still controversial. In this work, we examined whether the synthetic allosteric SIRT1 activator, SRT1720, may similarly attenuate D-GalN/LPS-induced hepatotoxicity. MATERIALS AND METHODS: Male Wistar rats were randomly assigned into 6 groups: (1) Control, (2) Quercetin, (3) SRT1720, (4) D-GalN/LPS, (5) Quercetin + D-GalN/LPS and (6) SRT1720 + D-GalN/LPS. After twenty-four hours, the effects of these treatments were evaluated by biochemical studies, real-time PCR and Western blot. RESULTS: D-GalN/LPS treatment downregulated SIRT1 expression and markedly increased the aminotransferase, bilirubin and conjugated diene levels. Conversely, quercetin and SRT1720 pretreatments upregulated SIRT1 expression and decreased the levels of the aforementioned markers. Quercetin had more profound effect on SIRT1 expression than SRT1720. Moreover, quercetin was more efficacious than SRT1720 in combatting the cytotoxic effects of D-GalN/LPS, as evidenced by lower markers of liver injury. CONCLUSIONS: These results strongly suggest the involvement of SIRT1 in the cytoprotective effects of quercetin and SRT1720 against D-GalN/LPS-induced hepatotoxicity.

• MeSH
• alanintransaminasa metabolismus   MeSH
• antioxidancia farmakologie   MeSH
• bilirubin metabolismus   MeSH
• down regulace účinky léků   MeSH
• galaktosamin škodlivé účinky   MeSH
• heterocyklické sloučeniny tetra- a více cyklické farmakologie   MeSH
• krysa rodu rattus MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lékové postižení jater farmakoterapie   MeSH
• lipopolysacharidy škodlivé účinky   MeSH
• náhodné rozdělení MeSH
• potkani Wistar MeSH
• quercetin farmakologie   MeSH
• sirtuin 1 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: The aim of our study was to evaluate the rate of surgical complications, patient outcomes, and impact on graft function in renal transplant recipients in whom cholecystectomy for acute cholecystitis was performed. METHODS: We reviewed data on transplant patients from January 1, 2006, to December 31, 2013. The subgroup of patients who required subsequent cholecystectomy for acute cholecystitis was assessed, and their data were further analyzed. RESULTS: Thirty-one patients who underwent cholecystectomy for acute cholecystitis after renal transplantation were included in the study. Clinical signs such as pain in the right upper quadrant, temperature >38°C, and elevation in bilirubin levels occurred in 20 (64.5%), 8 (25.8%), and 3 (9.7%) patients, respectively. Ultrasound signs of acute cholecystitis were present in 27 patients (87.1%). In terms of laboratory values, white blood cell counts >10 × 10(9)/L occurred in 17 patients (54.8%), and C-reactive protein levels >40 mg/L were reported in 21 patients (67.7%). The conversion rate to open surgery was 32.3% (10 patients). In 13 cases, acalculous cholecystitis was present (41.9%). The average serum creatinine level 1 year after cholecystectomy had no statistically significant differences. One patient required temporary dialysis during the postoperative period (with subsequent graft recovery), and 1 graft was lost. CONCLUSIONS: Acute cholecystitis in kidney transplant recipients is a serious complication, with frequent difficulties related to evaluation and diagnosis. Because clinical signs could be very mild compared with severity of gallbladder affliction, there is little room if any for conservative treatment in these patients. We have not noticed adverse impact of acute cholecystitis on 1-year graft function.

• MeSH
• akutní cholecystitida diagnostické zobrazování   chirurgie   MeSH
• C-reaktivní protein metabolismus   MeSH
• cholecystektomie laparoskopická metody   MeSH
• dialýza ledvin MeSH
• dospělí MeSH
• konverze na otevřenou operaci MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• počet leukocytů MeSH
• pooperační komplikace etiologie   chirurgie   MeSH
• přežívání štěpu MeSH
• retrospektivní studie MeSH
• senioři MeSH
• transplantace ledvin * MeSH
• ultrasonografie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The bilirubin (BR) photo-conversion in the human body is a protein-dependent process; an effective photo-isomerization of the potentially neurotoxic Z,Z-BR as well as its oxidation to biliverdin in the antioxidant redox cycle is possible only when BR is bound on serum albumin. We present a novel analytical concept in the study of linear tetrapyrroles metabolic processes based on an in-depth mapping of binding sites in the structure of human serum albumin (HSA). A combination of fluorescence spectroscopy, circular dichroism (CD) spectroscopy, and molecular modeling methods was used for recognition of the binding site for BR, its derivatives (mesobilirubin and bilirubin ditaurate), and the products of the photo-isomerization and oxidation (lumirubin, biliverdin, and xanthobilirubic acid) on HSA. The CD spectra and fluorescent quenching of the Trp-HSA were used to calculate the binding constants. The results of the CD displacement experiments performed with hemin were interpreted together with the findings of molecular docking performed on the pigment-HSA complexes. We estimated that Z,Z-BR and its metabolic products bind on two independent binding sites. Our findings support the existence of a reversible antioxidant redox cycle for BR and explain an additional pathway of the photo-isomerization process (increase of HSA binding capacity; the excess free [unbound] BR can be converted and also bound to HSA).

• MeSH
• bilirubin analogy a deriváty   chemie   metabolismus   MeSH
• biliverdin analogy a deriváty   chemie   metabolismus   MeSH
• cirkulární dichroismus MeSH
• fluorescenční spektrometrie MeSH
• fotochemické procesy * MeSH
• kompetitivní vazba MeSH
• lidé MeSH
• ligandy MeSH
• molekulární konformace MeSH
• molekulární modely * MeSH
• oxidace-redukce MeSH
• sérový albumin chemie   metabolismus   MeSH
• simulace molekulového dockingu MeSH
• stereoizomerie MeSH
• taurin analogy a deriváty   chemie   metabolismus   MeSH
• tryptofan chemie   MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• metabolismus MeSH

• Konspekt
• Fyziologie člověka a srovnávací fyziologie
• NLK Obory
• vnitřní lékařství

Studium nových terapeutických postupů při nekonjugovaných hyperbilirubinémií se zaměřením na identifikace faktorů zodpovědných za konverzi bilirubinu ve střevním lumen. Studium vlivu hyperbilirubinémie na organismus za podmínek oxidačního stresu.; Study of new therapeutical procedures in unconjugated hyperilirubinemias with focusing on identification of factors responsible for bilirubin conversion in intestinal lumen. Study of the influnce of hyperbilirubinemia on organism in the condition of oxidative stress.

• MeSH
• bilirubin metabolismus   MeSH
• hyperbilirubinemie terapie   MeSH
• nemoci jater MeSH
• urobilin MeSH

• Konspekt
• Lékařské vědy. Lékařství
• NLK Obory
• gastroenterologie
• terapie
• vnitřní lékařství
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

• MeSH
• diagnostické testy rutinní normy   MeSH
• mezinárodní soustava jednotek MeSH
• Publikační typ
• tabulky MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• biochemie

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• gastroenterologie