Large-scale surveillance study of the safety and effectiveness of entecavir in Korean patients with chronic hepatitis B.

BACKGROUND/AIMS: Entecavir (ETV) is effective and safe antiviral agent against hepatitis B virus (HBV) in clinical and real-world setting but, most studies were performed in single institute or have limitation in patient's number. A large-scale nation-wide real-world surveillance study was carried out to investigate safety, efficacy and clinical effectiveness of ETV in Korean patients with chronic hepatitis B (CHB). METHODS: Between 2006 and 2012, 3,444 patients were enrolled from 132 Korean institutions. For the safety assessment, investigators recorded the occurrence of observed and patient-reported adverse events (AEs), as well as laboratory abnormalities. Efficacy, which consisted of change in HBV DNA and alanine aminotransferase (ALT), was evaluated in patients who had received at least 16 weeks of ETV treatment. Overall clinical effectiveness, based on improvement of ALT, HBV DNA and patient's symptoms, was evaluated by physicians. RESULTS: Of the patients, 3,367 were evaluated for safety and 3,115 for efficacy and clinical effectiveness. Three hundred and eighty AEs were reported in 255 cases (7.57%), and 67 adverse drug reactions in 54 cases (1.6%). Serious AEs (SAE) were 19 events in nine cases (0.27%). Serious adverse drug reactions (SADR) were three events in two cases (0.06%), and unexpected SAE/SADR were three events in two cases (0.06%). Medical history and concomitant medications were factors inf luencing incidence rates of AEs. Overall clinical effectiveness rate was 96.53%, which was clinically assessed as marked improved or improved state. CONCLUSIONS: This study showed that ETV was well tolerated and clinically effective in Korean patients with CHB in a real-world nation-wide setting.

Efficacy and safety of entecavir versus lamivudine over 5 years of treatment: A randomized controlled trial in Korean patients with hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND/AIMS: Long-term data on antiviral therapy in Korean patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) are limited. This study evaluated the efficacy and safety of entecavir (ETV) and lamivudine (LAM) over 240 weeks. METHODS: Treatment-naive patients with HBeAg-negative CHB were randomized to receive ETV 0.5 mg/day or LAM 100 mg/day during the 96 week double-blind phase, followed by open-label treatment through week 240. The primary endpoint was the proportion of patients with virologic response (VR; hepatitis B virus [HBV] DNA<300 copies/mL) at week 24. Secondary objectives included alanine aminotransferase (ALT) normalization and emergence of ETV resistance (week 96), VR and log reduction in HBV DNA levels (week 240), and safety evaluation. RESULTS: In total, 120 patients (>16 years old) were included (ETV, n=56; LAM, n=64). Baseline characteristics were comparable between the two groups. A significantly higher proportion of ETV-treated patients achieved VR compared to LAM at week 24 (92.9% vs. 67.2%, P=0.0006), week 96 (94.6% vs. 48.4%, P<0.0001), and week 240 (95.0% vs. 47.6%, P<0.0001). At week 96, ALT normalization was observed in 87.5% and 51.6% of ETV and LAM patients, respectively (P<0.0001). Virologic breakthrough occurred in one patient (1.8%) receiving ETV and 26 patients (42.6%) receiving LAM (P<0.0001) up to week 96. Emergence of resistance to ETV was not detected. The incidence of serious adverse events was low and unrelated to the study medications. CONCLUSIONS: Long-term ETV treatment was superior to LAM, with a significantly higher proportion of patients achieving VR. Both treatments were well tolerated.

Evidence of carrier-mediated transport in the penetration of donepezil into the rat brain.

The objective of this study was to characterize the mechanism that controls the transport of donepezil into the brain. The apparent brain uptake clearance (CL(app,br)) was decreased as a function of the dose of donepezil, suggesting an involvement of a saturable transport process via transporter(s) in the penetration across the blood-brain barrier (BBB). Consistent with in vivo results, the uptake of substrates for organic cation transporters was significantly reduced by donepezil in both MBEC4 cells (i.e., a model for BBB) and HEK 293 cells expressing the transporters found in the brain, indicative of the involvement of organic cation transporters in the transport of the drug. Furthermore, donepezil transport was enhanced (p < 0.01) in HEK 293 cells expressing rOCNT1, rOCTN2, or rCHT1. The CL(app,br) was reduced up to 52.8% of the control in rats that had been pretreated with choline, while the CL(app,br) was unaffected with pretreatments with organic cations other than choline, suggesting that choline and donepezil share a common transport mechanism in the penetration across the BBB in vivo. Taken together, these observations suggest that the transport of donepezil across the BBB is mediated by organic cation transporters such as choline transport system(s).

Contribution of a significant first-pass effect of dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate in the liver to its poor bioavailability in rats.

OBJECTIVES: The objective of this study was to investigate the mechanism responsible for the poor oral bioavailability of dimethyl-4',4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB), a hepatoprotective agent, in rats. METHODS: DDB was intravenously administered to rats at doses of 0.2-1 mg/kg. To determine the hepatic first-pass effect in rats, DDB (1 mg/kg) was administered via the pyloric vein and the femoral vein. Direct measurement of intestinal permeability was attempted using Caco-2 cell monolayers and rat intestinal epithelium. KEY FINDINGS: A moment analysis indicated that the volume of distribution and clearance remained unchanged with the magnitude of the dose, indicating that DDB exhibited linear pharmacokinetics. When the area under the curve for DDB after administration to the pyloric vein was compared with that after femoral vein administration, the ratio (F(H)) was found to be 0.294, indicating a significant first-pass effect for DDB. The permeability of DDB was high in the rat intestine (1.78 +/- 0.229 x 10(-5) cm/s) and in Caco-2 cell monolayers (6.8 +/- 0.70 x 10(-5) cm/s), suggesting that DDB, in soluble form, was readily permeable across the intestinal epithelium. CONCLUSIONS: These observations indicated that despite the fact that DDB was readily permeable to the intestinal epithelium, a significant first-pass metabolism was associated with its pharmacokinetics in rats.

Saturable distribution of tacrine into the striatal extracellular fluid of the rat: evidence of involvement of multiple organic cation transporters in the transport.

The kinetics and mechanism by which tacrine is distributed in the rat brain were examined. Tacrine levels in plasma and striatal extracellular fluid were used to evaluate the pharmacokinetics of this process. The K(D,brain) was decreased with the dose for tacrine, indicating that the distribution to the brain is saturable. The uptake of organic cations such as choline, 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), and carnitine was inhibited by the addition of tacrine to cultures of mouse immortalized brain capillary endothelial cells. In addition, the apical to basal transport and basal to apical transport of tacrine were inhibited by the addition of organic cations to cultures of LLC-PK1 cells, suggesting that tacrine transport across the blood-brain barrier (BBB) is mediated by organic cation transport system(s). Consistent with the in vitro results, a standard reverse transcription-polymerase chain reaction procedure was able to amplify the message of mOCT2 and mOCTN2, but not mOCT1, in MBEC4 (mouse brain microvessel endothelial cell line 4) cells. Similarly, mRNAs for rOCT2 and rOCTN2 were present in representative rat brain samples. To determine whether OCT2 and/or OCTN2 transport tacrine, these transporters were cloned and then transfected in SK-HEP1 and HEK 293 cells. The uptake of choline, MPP, and TEA was inhibited by the presence of tacrine in rOCT2-expressing SK-HEP1 cells, whereas the uptake of carnitine was inhibited by the presence of tacrine in rOCTN2-expressing HEK 293 cells. Collectively, these observations suggest that the transport of tacrine across the BBB is mediated, at least in part, by multiple organic cation transport systems in rats.