Clinical usefulness of Mac-2 binding protein glycosylation isomer for diagnosing liver cirrhosis and significant fibrosis in patients with chronic liver disease: A retrospective single-center study.

Accurate diagnosis of liver cirrhosis (LC) and significant fibrosis in patients with chronic liver disease (CLD) is important. The Mac-2 binding protein glycosylation isomer (M2BPGi) has emerged as a novel serum biomarker for liver fibrosis; however, insufficient clinical data of M2BPGi are available in patients with CLD. Therefore, we performed a retrospective cohort study to investigate the clinical usefulness of serum M2BPGi for assessing LC and significant fibrosis in CLD patients. We retrospectively reviewed the CLD patients with measured serum M2BPGi at Kosin University Gospel Hospital between January 2016 and December 2019. Multivariate logistic regression analyses were conducted to identify the independent factors associated with LC. The diagnostic power of serum M2BPGi for LC and significant fibrosis (≥F2) was evaluated and compared to that of other serum biomarkers using receiver operating characteristic curve and area under the curve (AUC). A total of 454 patients enrolled in this study. M2BPGi (adjusted odds ratio [aOR], 1.77; 95% confidence interval [CI], 1.52-2.07) and fibrosis index based on four factors (aOR, 1.23; 95% CI, 1.11-1.37) were identified as significant independent factors for LC. The AUC of M2BPGi for LC (0.866) and significant fibrosis (0.816) were comparable to those of fibrosis index based on four factors (0.860, 0.773), aspartate aminotransferase-to-platelet ratio index (0.806, 0.752), and gamma-glutamyl transpeptidase-to-platelet ratio (0.759, 0.710). The optimal cut-off values for M2BPGi for LC and significant fibrosis were 1.37 and 0.89, respectively. Serum M2BPGi levels were significantly correlated with liver stiffness measurements (ρ = 0.778). Serum M2BPGi is a reliable noninvasive method for the assessment of LC and significant fibrosis in patients with CLD.

A Multi-Center, Double-Blind Randomized Controlled Phase III Clinical Trial to Evaluate the Antiviral Activity and Safety of DA-2802 (Tenofovir Disoproxil Orotate) and Viread (Tenofovir Disoproxil Fumarate) in Chronic Hepatitis B Patients.

BACKGROUND: Tenofovir disoproxil fumarate (TDF, Viread®) had been used as a standard treatment option of chronic hepatitis B (CHB). This clinical trial was conducted to evaluate the efficacy and safety of DA-2802 (tenofovir disoproxil orotate) compared to TDF. METHODS: The present study was a double blind randomized controlled trial. Patients with CHB were recruited from 25 hospitals in Korea and given DA-2802 at a dose of 319 mg once daily or Viread® at a dose of 300 mg once daily for 48 weeks from March 2017 to January 2019. Change in hepatitis B virus (HBV) DNA level at week 48 after dosing compared to baseline was the primary efficacy endpoint. Secondary efficacy endpoints were proportions of subjects with undetectable HBV DNA, those with normal alanine aminotransferase (ALT) levels, and those with loss of hepatitis B envelop antigen (HBeAg), those with loss of hepatitis B surface antigen (HBsAg). Adverse events (AEs) were also investigated. RESULTS: A total of 122 patients (DA-2802 group: n = 61, Viread® group: n = 61) were used as full analysis set for efficacy analysis. Mean age, proportion of males, laboratory results and virologic characteristics were not different between the two groups. The change in HBV DNA level at week 48 from baseline was -5.13 ± 1.40 in the DA-2802 group and -4.97 ± 1.40 log10 copies/mL in the Viread® group. The analysis of primary endpoint using the nonparametric analysis of covariance showed statistically significant results (P < 0.001), which confirmed non-inferiority of DA-2802 to Viread® by a prespecified noninferiority margin of 1. The proportion of undetectable HBV DNA was 78.7% in the DA-2802 group and 75.4% in the Viread® group (P = 0.698). The proportion of subjects who had normal ALT levels was 75.4% in the DA-2802 group and 73.3% in the Viread® group (P = 0.795). The proportion of those with HBeAg loss was 8.1% in the DA-2802 group and 10.8% in the Viread® group (P = 1.000). No subject showed HBsAg loss. The frequency of AEs during treatment was similar between the two groups. Most AEs were mild to moderate in severity. CONCLUSION: DA-2802 is considered an effective and safe treatment for patients with CHB. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02967939.

Effectiveness of Albumin-bilirubin Score as a Predictor of Post-hepatectomy Liver Failure in Patients with Hepatocellular Carcinoma.

Backgrounds/Aims: Post-hepatectomy liver failure (PHLF) is a major concern for patients with hepatocellular carcinoma (HCC) who have undergone liver resection. The albumin-bilirubin (ALBI) score is a novel model for assessing liver function. We aimed to investigate the effectiveness of the ALBI score as a predictor of PHLF in HCC patients who have undergone hepatectomy in South Korea. Methods: Between January 2014 and November 2018, HCC patients who underwent hepatectomy and indocyanine retention rate at 15 min (ICG-R15) test were enrolled in this study. Results: A total of 101 patients diagnosed with HCC underwent hepatectomy. Thirty-two patients (31.7%) experienced PHLF. The ALBI score (OR 2.83; 95% CI 1.22-6.55; p=0.015), ICG-R15 (OR 1.07; 95% CI 1.02-1.12; p=0.007) and ALBI grade (OR 2,86; 95% CI 1.08-7.58; p=0.035) were identified as independent predictors of PHLF by multivariable analysis. The area under the receiver operating characteristic curve of the ALBI score and ICG-R15 were 0.676 (95% CI 0.566-0.785) and 0.632 (95% CI 0.513-0.752), respectively. The optimal cutoff value of the ALBI score in predicting PHLF was -2.62, with a sensitivity of 75.0% and a specificity of 56.5%. Conclusions: The ALBI score is an effective predictor of PHLF in patients with HCC, and its predictive ability is comparable to that of ICG-R15.

[Gallbladder Perforation after Transarterial Chemoembolization in a Patient with a Huge Hepatocellular Carcinoma].

Transarterial chemoembolization (TACE) is a common treatment for unresectable hepatocellular carcinoma (HCC). The most common complications after TACE are non-specific symptoms called post-embolization syndrome, such as abdominal pain or fever. Rare complications, such as liver failure, liver abscess, sepsis, pulmonary embolism, cholecystitis, can also occur. On the other hand, gallbladder perforation is quite rare. This paper reports a case of gallbladder perforation following TACE. A 76-year-old male with a single 9-cm-sized HCC underwent TACE. Five days after TACE, he developed persistent right upper quadrant pain and ileus. An abdomen CT scan confirmed gallbladder perforation with bile in the right paracolic gutter and pelvic cavity. Percutaneous transhepatic gallbladder drainage was performed with the intravenous administration of antibiotics. After 1 month, the patient underwent right hemihepatectomy and cholecystectomy. Physicians should consider the possibility of gallbladder perforation, which is a rare complication after TACE, when unexplained abdominal pain persists.

Propofol alone prevents worsening hepatic encephalopathy rather than midazolam alone or combined sedation after esophagogastroduodenoscopy in compensated or decompensated cirrhotic patients.

BACKGROUND: This study was conducted to determine which type and dose of sedative drugs should be given to cirrhotic patients with compensation or decompensation during esophagogastroduodenoscopy (EGD) to prevent hepatic encephalopathy (HE) after sedation. METHODS: We reviewed the medical records of cirrhotic patients consecutively admitted to the hospital and conducted a number connection test (NCT) before and 2 h after EGD with moderate sedation. Sedation was performed using either propofol alone, midazolam alone, or combined propofol + midazolam. RESULTS: Sixty-seven patients were admitted for a screening EGD. The NCT before and after sedation were not significantly different in the propofol alone (pre-NCT = 47.3 ± 19.71 seconds vs. post-NCT = 49.4 ± 21.79 seconds, P = 0.6389). In the midazolam alone (pre-NCT = 50.3 ± 20.56 vs. post-NCT = 63.7 ± 33.17, P = 0.0021) and in the combined propofol + midazolam (pre-NCT = 47.4 ± 20.99 vs. post-NCT = 60.0 ± 30.79, P = 0.0002), NCT were significantly delayed. The propofol alone group received 52.3 ± 16.31 mg (0.82 ± 0.29 mg/kg). In 45 (67.2%) decompensated patients, only the propofol alone was not significantly different between pre-NCT (49.2 ± 22.92) and post-NCT (52.3 ± 24.90) (P = 0.4548). Serum sodium level was significantly correlated with delta-NCT (r = 0.3594, P = 0.0028). CONCLUSION: Propofol alone could be the best sedation strategy for cirrhotic patients with compensation or decompensation without aggravation of covert or overt HE. Hyponatremia could be a risk factor for developing or worsening HE after EGD with sedation.

Risk factors associated with hypophosphatemia in chronic Hepatitis B patients treated with tenofovir disoproxil fumarate.

Tenofovir disoproxil fumarate (TDF) is thought to cause varying degrees of hypophosphatemia in patients with chronic hepatitis B (CHB). Therefore, we investigated factors that cause hypophosphatemia in patients treated with TDF and methods to increase serum phosphorus concentrations in clinical practice.We completed a retrospective review of patients with CHB treated with TDF initially at Kosin University Gospel Hospital, Busan, Korea from January 2012 to January 2017. Subclinical hypophosphatemia and hypophosphatemia were defined as serum phosphorus below 3.0 mg/dL and 2.5 mg/dL, respectively.We screened 206 patients with CHB treated with TDF, among which 135 were excluded for the following reasons: baseline malignancy (59), limited data (50), co-administered other antivirals (14), hypophosphatemia at baseline (7), and other reasons (5). The final study population comprised 71 patients. Subclinical hypophosphatemia developed in 43 (60.5%) patients. Hypophosphatemia occurred in 18 patients (25.3%). Liver cirrhosis was the most significant predictor of hypophosphatemia (P = .038, OR = 3.440, CI = 1.082-10.937) Patients diagnosed with subclinical hypophosphatemia were encouraged to increase their intake of nuts and dairy products (25 patients) or reduce their alcohol intake (2), dose reduction of TDF (4) or placed under observation (4). Among patients with subclinical hypophosphatemia, serum phosphorus concentrations were elevated (>3.0 mg/dL) in 23 of 36 patients (63.8%). Increased nut and dairy intake increased phosphorus concentrations to more than 3.0 mg/dl in 16 of 25 patients (64.0%).Entecavir or tenofovir alafenamide fumarate (TAF) should be considered rather than TDF in patients with liver cirrhosis because of the risk of hypophosphatemia. Instead of stopping TDF treatment, encouraging increased intake of phosphorus-rich foods could increase serum phosphorus concentrations in clinical practice.

Percutaneous Transcholecystic Removal of Common Bile Duct Stones: Case Series in 114 Patients.

Purpose To evaluate the safety and effectiveness of percutaneous transcholecystic removal of common bile duct (CBD) stones in 114 patients. Materials and Methods This retrospective study was approved by the institutional review board. From September 2011 through February 2017, 114 consecutive patients (68 men, 46 women; mean age, 73 years) underwent percutaneous transcholecystic removal of CBD stones. All patients had acute cholangitis or cholecystitis. Stones were extracted through a 12-F sheath by using a Wittich nitinol stone basket uder fluoroscopic guidance. Technical success rates, complications, and long-term follow-up were evaluated. Results Technical success was achieved in 96 of 114 (84.2%) patients. In 18 patients, stone removal was unsuccessful due to failure of cystic duct cannulation (n = 11), proximal migration of the CBD stone (n = 3), multiple CBD stones (n = 3), and low insertion of the cystic duct (n = 1). No major procedure-related complications were seen. During the mean follow-up of 644 days (range, 11-2206 days), CBD stones recurred in 12 patients after a mean of 884 days (range, 439-1799 days) after the procedure. Conclusion Percutaneous transcholecystic removal of common bile duct stones seems to be a safe and effective method. © RSNA, 2018 Online supplemental material is available for this article . See also the editorial by vanSonnenberg and Panchanathan in this issue.

Baracle® vs Baraclude® for 48 weeks in patients with treatment-naïve chronic hepatitis B: a comparison of efficacy and safety.

BACKGROUND AND OBJECTIVE: Entecavir (ETV) is a standard of care for chronic hepatitis B (CHB). In a bioequivalence study, ETV from Dong-A ST (Baracle®) was found to have a pharmacokinetic profile equivalent to ETV from Bristol-Myers Squibb (BMS) (Baraclude®). The present study was conducted to evaluate the antiviral activity and safety of ETV from Dong-A ST in comparison to ETV from BMS in patients with CHB. METHODS: In this multicenter, double-blind, active-controlled, stratified-randomized, parallel group, comparative trial, 118 treatment-naïve patients with CHB were randomly assigned to receive either 0.5 mg of ETV from Dong-A ST or ETV from BMS once daily for 48 weeks. The primary efficacy endpoint was virologic improvement (a mean reduction from baseline in serum HBV DNA levels) at 24 weeks. Secondary efficacy endpoints included a mean reduction in serum HBV DNA levels at 48 weeks, proportion of patients with undetectable levels of serum HBV DNA, rates of hepatitis B e antigen (HBeAg) loss and seroconversion, rates of HBsAg loss and seroconversion, and rates of normalization of alanine aminotransferase (ALT) levels. RESULTS: From baseline to week 24, HBV DNA levels (log10) decreased by 4.81 and 4.63 with ETV from Dong-A ST and with ETV from BMS, respectively. The upper limit of two-sided 95% confidence intervals (CI) (equivalent to one-sided 97.5% CIs) for the difference between the treatment groups was 0.208, which was below the noninferiority margin of 1, thus supporting the noninferiority of ETV from Dong-A ST in comparison to ETV from BMS. No statistically significant differences were noted between the treatment groups in all secondary and tertiary efficacy endpoints. Safety profiles were also similar between the two groups. CONCLUSION: In patients with previously untreated HBeAg-positive or negative HBV infection, the efficacy of ETV from Dong-A ST was noninferior to that of ETV from BMS, and there were no significant differences in efficacy or safety between two groups.

Capsanthin Inhibits both Adipogenesis in 3T3-L1 Preadipocytes and Weight Gain in High-Fat Diet-Induced Obese Mice.

Adipogenesis in murine preadipocyte 3T3L-1 has been used as a model system to study anti-obese bioactive molecules. During adipogenesis in 3T3-L1 preadipocytes, we found that capsanthin inhibited adipogenesis (IC50; 2.5 µM) and also showed lipolytic activity in differentiated adipocytes from the preadipocytes (ED50; 872 nM). We identified that the pharmacological activity of capsanthin on adipogenesis in 3T3-L1 was mainly due to its adrenoceptor-ß2-agonistic activity. In high-fat diet animal model study, capsanthin significantly enhanced spontaneous locomotive activities together with progressive weight-loss. The capsanthin-induced activation of kinetic behavior in mice was associated with the excessive production of ATP initiated by both the enhanced lipolytic activity together with accelerated oxidation of fatty acids due to the adrenoceptor ß2-agonistic activity of capsanthin. Capsanthin also dose-dependently increased adiponectin and p-AMPK activity in high fat diet animals, suggesting that capsanthin has both anti-obesity and insulin sensitizing activities.

Barriers to treatment of failed or interferon ineligible patients in the era of DAA: single center study.

BACKGROUND/AIMS: Interferon-based treatment is not appropriate for a large number of patients with chronic hepatitis C for various medical and social reasons. Newly developed directly acting antivirals (DAAs) have been used to treat chronic hepatitis C without severe adverse effects and have achieved a sustained viral response (SVR) rate of 80-90% with short treatment duration. We were interested to determine whether all patients who failed to respond to or were ineligible for interferon-based therapy could be treated with DAAs. METHODS: Medical records of patients with positive serum anti-hepatitis C virus (HCV) or HCV RNA between January 2009 and December 2013 were reviewed. Demographic, clinical, and treatment data were collected for analysis. RESULTS: A total of 876 patients were positive for both anti-HCV and HCV RNA. Of these, 244 patients were eligible for interferon, although this was associated with relapse in 39 (16%) of patients. In total, 130 patients stopped interferon therapy (67% adverse effects, 28% non-adherent, 4% malignancy, 1% alcohol abuse) and 502 patients were ineligible (66% medical contraindications, 25% non-adherent, 5% socioeconomic problems). Among 671 patients who were ineligible for or failed to respond to interferon therapy, more than 186 (27.7%) could not be treated with DAA due to financial, social, or cancer-related conditions. CONCLUSIONS: Newly developed DAAs are a promising treatment for patients with chronic hepatitis C who are ineligible for or failed to respond to interferon-based therapy. Nevertheless, not all chronic hepatitis C patients can be treated with DAAs due to various reasons.

Percutaneous transluminal forceps biopsy in patients suspected of having malignant biliary obstruction: factors influencing the outcomes of 271 patients.

OBJECTIVES: To evaluate predictive factors for false-negative diagnosis of percutaneous forceps biopsies in patients suspected of having a malignant biliary obstruction METHODS: Two hundred seventy one consecutive patients with obstructive jaundice underwent percutaneous forceps biopsy. In each patient, three to five specimens (mean, 3.5 specimens) were collected from the lesion. The final diagnosis for each patient was confirmed with pathologic findings at surgery, additional histocytologic data, or clinical and radiologic follow-up. Univariate and multivariate logistic regression analysis was used to identify risk factors associated with false-negative diagnosis. RESULTS: One hundred ninety four of 271 biopsies resulted in correct diagnoses of malignancy, while 20 biopsy diagnoses were proved to be true-negative. There were 57 false-negative diagnoses and no false-positive diagnoses. The diagnostic performance of transluminal forceps biopsy in malignant biliary obstructions was as follows: sensitivity, 77.2%; specificity, 100%; and accuracy, 78.9%; positive predictive value, 100%, negative predictive value; 25.9%. Periampullary segment of common bile duct, intrahepatic bile duct and metastatic disease were the significant risk factors of false-negative diagnosis. CONCLUSIONS: Percutaneous forceps biopsy provides relatively high accuracy in the diagnosis of malignant biliary obstructions. The predictive factors of false-negative biopsy were determined to be biopsy site and origin of primary tumour. KEY POINTS: • Percutaneous forceps biopsy provides relatively high accuracy in diagnosis of malignant biliary obstructions. • The predictive factors of false-negative biopsy were biopsy site and origin of primary tumour. • The procedure-related complications were low.

Characteristics and Discrepancies in Acute-on-Chronic Liver Failure: Need for a Unified Definition.

BACKGROUND & AIM: To investigate the prevalence, mortalities, and patient characteristics of Acute-on-chronic liver failure (ACLF) according to the AARC (Asian Pacific Association for the Study of the Liver ACLF Research Consortium) and European Association for the Study of the Liver CLIF-C (Chronic Liver Failure Consortium) definitions. METHODS: We collected retrospective data for 1470 hospitalized patients with chronic liver disease (CLD) and acute deterioration between January 2013 and December 2013 from 21 university hospitals in Korea. RESULTS: Of the patients assessed, the prevalence of ACLF based on the AARC and CLIF-C definitions was 9.5% and 18.6%, respectively. The 28-day and 90-day mortality rates were higher in patients with ACLF than in those without ACLF. Patients who only met the CLIF-C definition had significantly lower 28-day and 90-day survival rates than those who only met the AARC definition (68.0% vs. 93.9%, P<0.001; 55.1% vs. 92.4%, P<0.001). Among the patients who had non-cirrhotic CLD, the 90-day mortality of the patients with ACLF was higher than of those without ACLF, although not significant (33.3% vs. 6.0%, P = 0.192). Patients with previous acute decompensation (AD) within 1- year had a lower 90-day survival rate than those with AD more than 1 year prior or without previous AD (81.0% vs. 91.9% or 89.4%, respectively, all P<0.001). Patients who had extra-hepatic organ failure without liver failure had a similar 90-day survival rate to those who had liver failure as a prerequisite (57.0% vs. 60.6%, P = 0.391). CONCLUSIONS: The two ACLF definitions result in differences in mortality and patient characteristics among ACLF patients. We suggest that non-cirrhotic CLD, previous AD within 1 year, and extra-hepatic organ failure should be included in the ACLF diagnostic criteria. In addition, further studies are necessary to develop a universal definition of ACLF.

Hepatitis C virus (HCV) genotypes and the influence of HCV subtype 1b on the progression of chronic hepatitis C in Korea: a single center experience.

BACKGROUND/AIMS: There is some controversy regarding whether or not hepatitis C virus (HCV) subtype 1b is more influential than non-1b subtypes on the progression of chronic hepatitis (CH) C to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 823 patients with chronic HCV infection, including 443 CH patients, 264 LC patients, and 116 HCC patients, who were HCV RNA positive and HBsAg negative. These patients had not received any prior treatment with either interferon alone or a combination of interferon and ribavirin. RESULTS: HCV subtypes 1b (51.6%) and 2a/2c (39.5%) were the two most common genotypes. The proportions of genotypes 2 (2a/2c, 2b, and 2) and 3 were 45.8% and 1.1%, respectively. One case of genotype 4 was found. HCV subtype 1b (47.3%) was less common than the non-1b subtypes (52.7%) in non-LC patients, but its proportion (56.9%) was higher than that of non-1b subtypes (43.1%) in LC patients (P=0.006). The proportions of patients with HCV subtype 1b did not differ significantly between the LC (55.3%) and HCC (60.3%) groups. Older age, male gender, and the relative progression of liver damage (non-LC vs. compensated LC vs. decompensated LC) were significant risk factors for HCC, with odds ratios of 1.081 (95% confidence interval [CI], 1.056-1.106), 5.749 (95% CI, 3.329-9.930), and 2.895 (95% CI, 2.183-3.840), respectively. HCV subtype 1b was not a significant risk factor for HCC (odds ratio, 1.423; 95% CI, 0.895-2.262). CONCLUSIONS: HCV subtypes 1b and 2a/2c were the two most common HCV genotypes. HCV subtype 1b seemed to be more influential than non-1b subtypes on the progression of CH to LC, but not on the development of HCC from LC.

Mucinous cystadenoma of the liver with ovarian-like stroma: the need for complete resection.

Cystadenoma of the liver is a rare neoplasm. Although many cystadenomas are asymptomatic, symptoms can include abdominal pain, postprandial epigastric discomfort, and nausea. Dramatic changes in hepatic imaging techniques have been helpful for diagnosing cystic lesions of the liver, such as simple cyst, hydatid cyst, cystadenoma, cystadenocarcinoma, and metastatic neuroendocrine tumors. However, it remains difficult to differentiate cystadenoma from cystadenocarcinoma for multiseptated cystic hepatic lesions with papillary projection on computed tomography (CT) and magnetic resonance imaging (MRI). Here we report the case of a 47-year-old woman with several months of postprandial discomfort and abdominal fullness. CT and MRI revealed multiseptated cystic lesions with papillary excrescences. A left hemihepatectomy was performed. Histology showed a benign mucinous cystic tumor with ovarian-like stroma.

Clevudine-induced viral response, associated with continued reduction of HBsAg titer, was durable after the withdrawal of therapy.

BACKGROUND: This study was conducted to evaluate the durability of clevudine-induced viral response after the withdrawal of treatment. METHODS: Patients who showed a complete response [alanine aminotransferase (ALT) normalization and hepatitis B virus (HBV) DNA <4,700 copies/mL for hepatitis B envelope antigen (HBeAg)-negative patients; ALT normalization, HBV DNA <4,700 copies/mL, and HBeAg seroconversion for HBeAg-positive patients] in the previous clevudine phase III trials were followed for an additional 96 weeks without any treatment for hepatitis B. RESULTS: Of the 63 patients in the study cohort, 73% and 35% of the patients had HBV DNA <141,500 and <4,700 copies/mL, respectively, and 75% of the patients had normal ALT at the end of follow-up. HBeAg seroconversion was maintained in 81% of the patients and hepatitis B surface antigen (HBsAg) loss occurred in 3 patients. Continued HBsAg titer decrease (-0.5 log IU/mL) was observed in the sustained viral responders, suggesting the reduction of covalently closed circular DNA in hepatocytes. CONCLUSIONS: The clevudine-induced viral response was durable in the majority of patients for 2 years after the withdrawal of treatment.

Platelet-activating factor (PAF) receptor binding antagonists from Alpinia officinarum.

The bioassay-guided purification of ether extracts of Alpinia officinarum led to the isolation of two new compounds 6-hydroxy-1,7-diphenyl-4-en-3-heptanone (1) and 6-(2-hydroxy-phenyl)-4-methoxy-2-pyrone (4) as well as three known compounds 1,7-diphenyl-4-en-3-heptanone (2), 1,7-diphenyl-5-methoxy-3-heptanone (3), and apigenin (5). Their structures were established on the basis of spectral methods. All three diarylheptanoids 1, 2, and 3 exhibited potent PAF receptor binding inhibitory activities with an IC(50) of 1.3, 5.0, and 1.6 microM, respectively. These studies have identified diarylheptanoids as a novel class of potent PAF antagonists.

Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression.

UNLABELLED: Clevudine is a pyrimidine analog with potent and sustained antiviral activity against HBV. In the present study, we evaluated the safety and efficacy of clevudine 30 mg daily for 24 weeks and assessed the durability of antiviral response for 24 weeks after cessation of dosing in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB). We randomized a total of 86 patients (3:1) to receive clevudine 30 mg (n = 63) or placebo (n = 23) daily for 24 weeks. We followed patients for an additional 24 weeks after withdrawal of treatment. The median changes in HBV DNA from baseline were -4.25 and -0.48 log(10) copies/mL at week 24 in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy, with 3.11 log(10) reduction at week 48. At week 24 and week 48, 92.1% and 16.4% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (<300 copies/mL). The proportion of patients who achieved ALT normalization was 74.6% and 33.3% in the clevudine and placebo groups at week 24, respectively (P = 0.0006). ALT normalization in the clevudine group was well-maintained during the post-treatment follow-up period. The incidence of adverse events was similar in the 2 groups. No resistance to clevudine was detected during treatment. CONCLUSION: A 24-week clevudine therapy was well-tolerated and showed potent and sustained antiviral effect without evidence of viral resistance in e-CHB patients. However, treatment for longer than 24 weeks would be needed to achieve durable remission.

Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B.

UNLABELLED: Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24 weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A total of 243 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were randomized (3:1) to receive clevudine 30 mg once daily (n=182) or placebo (n=61) for 24 weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA reductions from baseline at week 24 were 5.10 and 0.27 log10 copies/mL in the clevudine and placebo groups, respectively (P<0.0001). Viral suppression in the clevudine group was sustained off therapy, with 3.73 log10 reduction at week 34 and 2.02 log10 reduction at week 48. At week 24, 59.0% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who achieved normalization of alanine aminotransferase (ALT) levels was 68.2% in the clevudine group and 17.5% in the placebo group at week 24 (P<0.0001). ALT normalization in the clevudine group was well maintained during post-treatment follow-up period. The incidence of adverse events (AEs) was similar between the clevudine group and the placebo group. No resistance to clevudine was detected with 24 weeks of administration of drug. CONCLUSION: A 24-week clevudine therapy was well tolerated and showed potent and sustained antiviral effect without evidence of viral resistance during treatment period in HBeAg-positive chronic hepatitis B.

Inhibition of calmodulin-dependent protein kinase II by cyclic and linear peptide alkaloids from Zizyphus species.

The effects of sedative peptide alkaloids from Zizyphus species on calmodulin- dependent protein kinase II were investigated. Protein kinase II activity was assayed on the basis of its ability to activate tryptophan 5-monooxygenase as its substrate in the presence of calmodulin. All thirteen alkaloids tested were stronger inhibitors than chlorpromazine (IC50, 98 microM) on calmodulin-dependent protein kinase II. Among them, the most potent inhibitor was daechuine S27 (IC50 2.95 microM), which was stronger than pimozide (IC50, 15.0 microM).

[The clinical meaning of the emergence of viral breakthrough during lamivudine treatment in patients with hepatitis B virus related chronic liver disease].

BACKGROUND/AIMS: Viral breakthrough has been considered a major limitation of lamivudine in the treatment of hepatitis B virus related chronic liver disease. Its clinical meaning has not been thoroughly assessed. METHODS: 64 patients who showed viral breakthrough during lamivudine treatment were retrospectively reviewed. We evaluated the rate of HBeAg seroconversion and hepatic decompensation after viral breakthrough. RESULTS: After viral breakthrough, serum alanine transaminase (ALT) elevation more than 1.2 x upper limit of normal (ULN) was noticed in 40 patients (62.5%). Acute flare (serum ALT elevation > x 5 ULN, or serum bilirubin >3 mg/dL) occurred in 15 patients (23.4%). During the period of follow up (15.0 +/- 9.7 months; range, 0-31 months) since viral breakthrough, decreased serum HBV-DNA level to below the detection limit and serum ALT normalization was seen in 15 patients (23.4%). HBeAg seroconversion was noticed in 7 (13.7%) of a total of 51 HBeAg positive patients at base line; in 4 (15.4%) of 26 patients with non-hepatic failure (chronic hepatitis or Child-Pugh class A liver cirrhosis) at base line; and in 2 (40.0%) of 5 patients with non-hepatic failure at base line and acute flare after viral breakthrough. During this period, terminal hepatic decompensation (Child-Pugh class C) or death was noticed in 9 (90.0%) of 10 patients who had hepatic decompensation (Child-Pugh class B or C) at baseline and acute flare after viral breakthrough. CONCLUSIONS: Acute flare after viral breakthrough seemed to continue during HBeAg seroconversion and rarely developed into terminal hepatic decompensation or death in patients with non-hepatic decompensation at baseline. Its incidence is not only high but lethal to most patients with hepatic decompensation at baseline.