entecavir Dotaz Zobrazit nápovědu
Protivirová léčba chronické hepatitidy B interferony byla v poslední dekádě významně rozšířena o syntetické nukleosidy a nukleotidy, které se podávají per os. Prvním lékem byl lamivudin (100 mg/den), druhým adefovir dipivoxil (10 mg/den) a v současné době probíhají rozsáhlé klinické studie s entecavirem (0,5 mg/den), což je guanosinový analog s velkou a selektivní protivirovou aktivitou proti viru hepatitidy B. Je indikován u HBeAg pozitivních i negativních pacientů s chronickou hepatitidou B a známkami virové replikace. Při porovnání výsledků léčby entecavirem a lamivudinem nastalo po 12 měsících léčby významné histologické, virologické a biochemické zlepšení, které bylo vyšší u entecaviru. Bezpečnost a snášenlivost léčby byly u obou léků podobné, a zatím nebyla zjištěna po léčbě entecavirem žádná rezistence proti viru hepatitidy B.
The antiviral treatment of chronic hepatitis B by interferons was significantly extended in last decade by synthetic nucleosides and nucleotides which are given perorally. Lamivudin (100 mg/day) was the first, adefovir dipivoxil (10 mg/dax) was the second drug, and nowadays extensive clinical trials are continuing with entecavir (0.5 mg/day) which is an analogue of guanosine with high and selective antiviral activity against hepatitis B virus. It is given to HBeAg positive and negative patients with chronic hepatitis B and serological markers of viral replication. In comparison of entecavir to lamivudine treatment there was significantly higher histological, virological and biochemical improvement in entecavir. Safety and tolerance profil was similar in both drugs and no antiviral resistence to hepatitis B virus was meanwhile observed during 12 moths entecavir treatment.
Nákaza virem hepatitidy B (HBV) je celosvětově jednou z nejvýznamnějších infekcí, jejímiž největšími riziky je progrese onemocnění do stadia pokročilé fibrózy či cirhózy s rizikem její dekompenzace a rozvoj hepatocelulárního karcinomu. Ve většině vyspělých zemí dochází v současnosti k poklesu incidence nových případů (nákaz) HBV v důsledku vakcinace. Používané léky se liší v indikacích (především IFN vs. antivirotika), v účinnosti a riziku rozvoje rezistence. Léčba entecavirem je účinná, efektivní, velmi bezpečná a vede k signifikantnímu poklesu virémie (resp. její negativizaci) během prvních 52 týdnů léčby, který trvá minimálně následujících 5 let léčby. Vznik rezistenze je vzácný, u pacientů s již vytvořenou rezistencí na lamivudin mohou být vyšší dávky entecaviru účinné
Hepatitis B (HBV) virus infection is one of the most important infections worldwide and is mainly associated with the risk of chronic hepatitis B that progresses into the stage of advance fibrosis or cirrhosis, often decompensating with the resulting development of hepatocellular carcinoma. Most advanced countries currently experience declining incidence rates of new cases (infections) with HBV as a result of vaccination. Drugs used to treat the condition differ in their indications (mainly IFN vs. antiviral drugs), their efficacy and resistance development. Treatment with entecavir is efficacious, effective, very safe and results in significantly reduced viraemia (or the virus becoming negative) within the first 52 weeks of treatment that should be continued for at least another 5 years. Resistance development is rare, and patients resistant to lamivudine may be effectively treated with higher entecavir doses.
- MeSH
- antivirové látky * farmakologie škodlivé účinky terapeutické užití MeSH
- chronická nemoc * farmakoterapie MeSH
- guanin * analogy a deriváty farmakologie škodlivé účinky terapeutické užití MeSH
- hepatitida B - antigeny e MeSH
- hepatitida B * farmakoterapie komplikace MeSH
- hodnocení léčiv MeSH
- incidence MeSH
- klinické zkoušky jako téma MeSH
- lamivudin MeSH
- léková rezistence MeSH
- lidé MeSH
- virová hepatitida u lidí * farmakoterapie komplikace MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
Celosvětově se během svého života nakazí více než dvě miliardy osob virem hepatitidy B (HBV) a v současnosti je chronicky infikováno 350–400 milionů lidí. Pokud infekce HBV trvá déle než šest měsíců, hovoříme o chronické hepatitidě B. Do chronicity přechází hepatitida B u více než 90 % novorozenců infikovaných vertikálně od matky v průběhu porodu či kojení, 20–30 % infekcí v dětském věku a 1–5 % infekcí u imunokompetentních dospělých osob. Vzhledem k tomu, že v České republice onemocní akutní hepatitidou B ročně 300–400 osob, a to v drtivé většině dospělých a jinak zdravých lidí, dá se odhadnout, že počet nově vzniklých chronických hepatitid B je v České republice velmi nízký a pohybuje se okolo 20 případů ročně.
- MeSH
- chronická hepatitida B farmakoterapie MeSH
- guanin analogy a deriváty farmakologie terapeutické užití MeSH
- hepatitida B epidemiologie farmakoterapie MeSH
- hodnocení léčiv MeSH
- léková rezistence MeSH
- lidé MeSH
- renální insuficience MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- klinické zkoušky MeSH
- směrnice pro lékařskou praxi MeSH
- Publikační typ
- abstrakt z konference MeSH
Two fast, simple, selective and economical sample preparation methods for the determination of entecavir in biological materials available at low amounts are reported. The choice of optimal extraction techniques was performed with regard to analyte hydrophilicity, sample volumes, selectivity, method recovery and rapidity. The compatibility of the eluate with the hydrophilic interaction chromatography (HILIC) mobile phase was crucial to allow the elimination of the evaporation and reconstitution steps and to obtain acceptable peak shapes. Different types of sorbents were employed for the extraction of two biological materials (plasma and plasma ultrafiltrate). The mixed-mode polymeric sorbent MCX was chosen as a suitable one for the solid phase extraction (SPE) of plasma samples. The analytes were eluted with 1ml of the mixture of 5 % ammonium hydroxide in ACN:water (95:5). Protein precipitation (PP) with 1ml of ACN was used to remove proteins from 500μl of plasma sample prior to SPE extraction. The microextraction by packed sorbent (MEPS) was employed for the cleaning up of plasma ultrafiltrate samples due to very small volumes available for the analysis. MEPS implemented a novel sorbent based on porous graphitic carbon, semi-automatic analytical syringe and a small volume of sample (50μl). The elution step was performed using 100μl of the mixture of 5mM ammonium acetate pH 4.0:ACN (25:75). The MEPS eluate was fully compatible with HILIC mobile phase subsequently used for the analysis of entecavir, unlike SPE eluate, which had to be evaporated and reconstituted in mobile phase. Both analytical methods were validated and demonstrated good linearity in a range 1-100ng/ml (r(2)>0.9992) for plasma samples and in a range 0.5-100ng/ml (0.9991) for the plasma ultrafiltrate samples. Intra-day accuracy expressed as recovery was within the range from 80-98% for the plasma samples and 97-106% for the plasma ultrafiltrate samples. Inter-day accuracy ranged within 81-106% for the plasma and 95-101% for the plasma ultrafiltrate samples. The intra-day precision expressed as the % of RSD was lower than 4% for both matrices and inter-day precision was lower than 7% for plasma and lower than 17% for plasma ultrafiltrate. Method sensitivity reached LLOQ of 1ng/ml in plasma and 0.5ng/ml in plasma ultrafiltrate samples. The method was applied for the determination of concentration-time profiles of entecavir in plasma of the perfusate for rat kidney perfusion and for the measurement of concentration of entecavir in plasma ultrafiltrate samples. The results should be helpful in the evaluation of excretion mechanism of entecavir.
- MeSH
- acetonitrily chemie MeSH
- adsorpce MeSH
- antivirové látky krev farmakokinetika MeSH
- chemické techniky analytické MeSH
- chromatografie MeSH
- guanin analogy a deriváty krev farmakokinetika MeSH
- hydrofobní a hydrofilní interakce MeSH
- krysa rodu rattus MeSH
- limita detekce MeSH
- mikroextrakce na pevné fázi MeSH
- potkani Wistar MeSH
- referenční standardy MeSH
- reprodukovatelnost výsledků MeSH
- rozpouštědla MeSH
- tandemová hmotnostní spektrometrie MeSH
- ultrafiltrace MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Entecavir is a deoxyguanosine nucleotide antiviral agent with the activity against hepatitis B virus (HBV). The agent possesses a polar structure, which is predetermined for hydrophilic interaction chromatography (HILIC). Novel, fast and sensitive HILIC-UHPLC method developed in this study included separation from matrix component on BEH Amide stationary phase by isocratic elution using binary mobile phase composed of acetonitrile/5mM ammonium acetate pH 4.0 (75:25) at flow-rate 0.3 ml/min. Analysis under RP-UHPLC conditions was also possible on BEH C18 stationary phase with mostly aqueous binary mobile phase composed of (4:96) acetonitrile/0.01% formic acid. The comparison of sensitivity of the two UHPLC-MS/MS methods both using selected reaction monitoring (SRM) for quantitation revealed only slightly higher sensitivity for HILIC determination, however much better method linearity, repeatability and accuracy. HILIC separation mode provided also more convenient conditions for straightforward coupling with solid phase extraction (SPE). Entecavir was extracted on Oasis HLB cartridge (1 ml, 30 mg) and eluted by 75% acetonitrile in water, which is actually the HILIC mobile phase used in this study. Therefore the evaporation/reconstitution step was omitted, which substantially accelerated the sample preparation step. The method was validated using stable isotopically labeled internal standard entecavir-C(2)(13) N(15), which is the most appropriate internal standard. Validation results demonstrated good method accuracy (with < 5% error, and 26% at LOQ), recovery (87-114%), precision (<4% RSD), selectivity and sensitivity (LOQ=100 pg/ml). The matrix effects determined by both post-column infusion method as well as post-extraction addition method were negligible (<15%).
- MeSH
- extrakce na pevné fázi MeSH
- guanin analogy a deriváty farmakokinetika moč MeSH
- hydrofobní a hydrofilní interakce MeSH
- krysa rodu rattus MeSH
- limita detekce MeSH
- lineární modely MeSH
- reprodukovatelnost výsledků MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
Entecavir (ETV) is one of the most potent agents for the treatment of the hepatitis B viral infection. The drug is principally eliminated by the kidney. The goal of this study was to investigate the potential of ETV to interact in vitro with the renal SLC transporters hOAT1, hOCT2, hCNT2 and hCNT3. Potential drug-drug interactions of ETV at the renal transporters with antiviral drugs known to be excreted by the kidney (adefovir, tenofovir, cidofovir) as well as transporter-dependent cytotoxicity were also examined. Interactions with the selected transporters along with cytotoxicity were studied in several transiently transfected cellular models using specific substrates and inhibitors. ETV was found to be both a substrate and inhibitor of hOAT1 (IC50 = 175.3 μM), hCNT2 (IC50 = 241.9 μM) and hCNT3 (IC50 = 278.4 μM) transporters, although it interacted with the transporters with relatively low affinities. ETV inhibited the cellular uptake of adefovir, tenofovir, and cidofovir by hOAT1; however, effective inhibition was shown at ETV concentrations exceeding therapeutic levels. In comparison with adefovir, tenofovir, and cidofovir, ETV displayed no transporter-mediated cytotoxicity in cells transfected with hOAT1, hCNT2, and hCNT3. No significant interaction of ETV with hOCT2 was detected. The study demonstrates interactions of ETV with several human renal transporters. For the first time, an interaction of ETV with the hCNTs was proved. We show that the potency of ETV to cause nephrotoxicity and/or clinically significant drug-drug interactions related to the tested transporters is considerably lower than that of adefovir, tenofovir, and cidofovir.
- Publikační typ
- časopisecké články MeSH
The nucleoside analog entecavir (ETV) is a first-line pharmacotherapy for chronic hepatitis B in adult and pediatric patients. However, due to insufficient data on placental transfer and its effects on pregnancy, ETV administration is not recommended for women after conception. To expand knowledge of safety, we focused on evaluating the contribution of nucleoside transporters (NBMPR sensitive ENTs and Na+ dependent CNTs) and efflux transporters, P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and multidrug resistance-associated transporter 2 (ABCC2), to the placental kinetics of ETV. We observed that NBMPR and nucleosides (adenosine and/or uridine) inhibited [3H]ETV uptake into BeWo cells, microvillous membrane vesicles, and fresh villous fragments prepared from the human term placenta, while Na+ depletion had no effect. Using a dual perfusion study in an open-circuit setup, we showed that maternal-to-fetal and fetal-to-maternal clearances of [3H]ETV in the rat term placenta were decreased by NBMPR and uridine. Net efflux ratios calculated for bidirectional transport studies performed in MDCKII cells expressing human ABCB1, ABCG2, or ABCC2 were close to the value of one. Consistently, no significant decrease in fetal perfusate was observed in the closed-circuit setup of dual perfusion studies, suggesting that active efflux does not significantly reduce maternal-to-fetal transport. In conclusion, ENTs (most likely ENT1), but not CNTs, ABCB1, ABCG2, and ABCC2, contribute significantly to the placental kinetics of ETV. Future studies should investigate the placental/fetal toxicity of ETV, the impact of drug-drug interactions on ENT1, and interindividual variability in ENT1 expression on the placental uptake and fetal exposure to ETV.
- MeSH
- ABC transportér z rodiny G, člen 2 metabolismus MeSH
- dítě MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- membránové transportní proteiny metabolismus MeSH
- nádorové proteiny metabolismus MeSH
- nádory prsu * metabolismus MeSH
- nukleosidy metabolismus farmakologie MeSH
- P-glykoprotein metabolismus MeSH
- P-glykoproteiny metabolismus MeSH
- placenta * metabolismus MeSH
- potkani Wistar MeSH
- protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
- proteiny přenášející nukleosidy metabolismus farmakologie MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům metabolismus MeSH
- těhotenství MeSH
- uridin MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
