One hundred and ninety-two weeks treatment of entecavir maleate for Chinese chronic hepatitis B predominantly genotyped B or C.

BACKGROUND: Entecavir (ETV) is a potent and selective nucleotide analog with significant activity against hepatitis B virus (HBV). ETV maleate is a derivative compound of ETV and was reported to have an efficacy and safety profile that is comparable to ETV (Baraclude) when used in Chinese patients with chronic hepatitis B (CHB) in phase III clinical trials (Clinical Trials.gov number, NCT01926288) at weeks 48, 96, and 144. AIM: To investigate the antiviral potency and safety of ETV maleate at week 192 in Chinese CHB patients predominantly genotyped B or C. METHODS: In this double-blind study, we randomly assigned patients to receive 0.5 mg/d ETV (Group A) or ETV maleate (Group B) (ratio, 1:1), each with a placebo tablet for 48 wk. Then, all patients received open-label treatment with 0.5 mg/d ETV maleate starting at week 49. The primary efficacy endpoint was the reduction in HBV DNA levels from baseline. Secondary endpoints included the proportion of patients with undetectable HBV DNA (< 20 IU/mL), serologic response, serum alanine aminotransferase (ALT) normalization and development of resistance mutations. RESULTS: Two hundred eighteen patients who were hepatitis B e antigen (HBeAg) positive and 57 who were HBeAg negative were analyzed and predominantly presented with genotype B (49.82%) or C (48.73%). For the HBeAg-positive CHB patients, the mean HBV DNA level decrease (6.61 Log10 IU/mL vs 6.69 Log10 IU/mL, P > 0.05), viral suppression with HBV DNA < 20 IU/mL (83.33% vs 79.17%, P > 0.05) and HBeAg seroconversion (28.77% vs 20.00%, P > 0.05) occurred similarly between Groups A and B at week 192. However, there was a significant difference in the proportion of patients with normal ALT levels (91.14% vs 78.38%, P < 0.05). For the HBeAg-negative CHB patients, no significant difference was found between Groups A and B at week 192 in terms of reductions in HBV DNA levels from baseline (6.05 Log10 IU/mL vs 6.03 Log10 IU/mL, P > 0.05), percentages of patients who achieved undetectable HBV DNA (100% vs 100%, P > 0.05) and rates of ALT normalization (95.65% vs 100.00%, P > 0.05). Safety and adverse event profiles were similar between Groups A and B. Two HBeAg-positive patients in Group A and 5 in Group B developed genotypic resistance to ETV. CONCLUSION: Long-term ETV maleate treatment for up to 192 wk is effective and safe in Chinese CHB patients predominantly genotyped as B or C.

240-week entecavir maleate treatment in Chinese chronic hepatitis B predominantly genotype B or C.

This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double-blind, double-dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty-seven (71 in group A) patients with HBeAg-positive CHB and 46 (21 in group A) patients with HBeAg-negative CHB completed the 240-week treatment and follow-up. Baseline characteristics were well balanced between the two groups. For the HBeAg-positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log10 IU/ml vs. B: by 6.74 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA (<20 IU/ml) at Week 240 were similar between groups (A:91.55% vs. B:87.88%; p > .05). Both groups achieved similar HBeAg seroconversion rates at week 240 (A:26.98% vs. B:20.97%; p > .05). Both groups achieved similar normalization of ALT (A:87.32% vs. B:83.61%; p > .05) at Week 240 (p > .05). For the HBeAg-negative CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.05 log10 IU/ml vs. B: by 6.10 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA at Week 240 were similar between groups (A:100% vs. B:100%). Both groups achieved similar normalization rates (A:90.91% vs. B: 95.45%; p > .05) of ALT at Week 240 (p > .05). In conclusion, long-term ETV maleate treatment was safe and efficient in Chinese CHB predominantly of genotype B or C.

Tenofovir disoproxil fumarate in Chinese chronic hepatitis B patients: Results of a multicenter, double-blind, double-dummy, clinical trial at 96 weeks.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is a prodrug of a nucleotide analogue. As an antiviral drug, TDF has been proposed in the first-line treatment of chronic hepatitis B (CHB). Qingzhong, a brand name of TDF, commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd., and Viread, another brand name of TDF, commercialized by GlaxoSmithKline, have both been approved by the State Food and Drug Administration, China. AIM: To investigate the efficacy and safety of the two TDF agents in the treatment of Chinese CHB patients. METHODS: This trial was registered at ClinicalTrials.gov with the identifier number of NCT02287857. A total of 330 Chinese CHB patients, among which 232 were hepatitis B e antigen (HBeAg)-positive, were included in this 5-year-long, multicenter, double-blinded, double-dummy, randomized-controlled, non-inferiority phase III trial. The participants were initially randomized into two groups: Group A (n = 161), in which the participants received 300 mg Qingzhong once a day for 48 wk; and Group B, in which the participants received 300 mg Viread once a day for 48 wk. Starting from week 49, all the participants in Groups A and B received 300 mg Qingzhong once a day until the 96th week. In this study, the primary endpoint was the decrease in plasma level of hepatitis B virus (HBV) DNA at the 96th week, while the secondary endpoints were suppression of HBV replication, alanine aminotransferase (ALT) normalization, HBeAg loss, and HBeAg seroconversion rates. RESULTS: For the participants with HBeAg-positive CHB, the decrease in mean HBV DNA level relative to the baseline value was comparable between Groups A and B (5.77 vs 5.73 log10 IU/mL, P > 0.05) at the 96th week. In addition, similar percentages of HBeAg-positive participants in the two groups exhibited undetectable levels of HBV DNA, HBeAg loss, and HBeAg seroconversion (71.05% vs 77.97%, 31.00% vs 27.27%, and 20.22% vs 15.79%, respectively, in Group A vs Group B; P > 0.05). For the participants with HBeAg-negative CHB, the decrease in mean HBV DNA level relative to the baseline value was also comparable between Groups A and B (4.46 vs 4.70 log10 IU/mL, P > 0.05) at the 96th week. In addition, similar percentages of HBeAg-negative participants in the two groups exhibited undetectable levels of HBV DNA (87.23% vs 94.12% in Group A vs Group B, respectively; P > 0.05). Finally, similar percentages of CHB patients (HBeAg-positive or HBeAg-negative) in the two groups exhibited normalization of ALT (80.14% vs 84.57% in Group A vs Group B, respectively; P > 0.05), and similar incidences of adverse events were observed (106 vs 104 in Group A vs Group B, respectively; P > 0.05). CONCLUSION: Both Qingzhong and Viread are effective and safe in the treatment of Chinese CHB patients according to the results of our clinical trial.

A randomized, double-blind, double-dummy, controlled, multicenter study of Qingzhong (tenofovir disoproxil fumarate) versus Viread for the treatment of chronic hepatitis B: First-stage results at week 48.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) has been widely recommended as a first-line antiviral agent to treat chronic hepatitis B (CHB). Qingzhong and Viread, formulations of TDF commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd and GlaxoSmithKline, respectively, have both been approved by the State Food and Drug Administration, China. This study analyzed the efficacy and safety of these 2 TDF agents in Chinese patients with CHB. METHODS: In this multicenter, randomized, double-blind, double-dummy, noninferiority phase 3 clinical trial (ClinicalTrials.gov identifier: NCT02287857), 330 Chinese patients with CHB [hepatitis B envelope antigen-positive (HBeAg) (+): 232] were randomly assigned to receive Qingzhong (group A: 161 patients) or Viread (group B: 169 patients) 300 mg once daily for 48 weeks. Subsequently, all patients were administered Qingzhong 300 mg once daily from week 49 to week 240. The primary end point was the degree of decline of plasma hepatitis B virus (HBV) DNA levels at week 48 and the secondary endpoints were viral suppression, normalization of alanine aminotransferase (ALT) levels, hepatitis B surface antigen (HBsAg)/HBeAg loss or seroconversion, and virological breakthrough. RESULTS: Among patients with CHB who were HBeAg (+), the mean HBV DNA titer decreased similarly between the groups at week 48. The percentages of patients who achieved undetectable HBV DNA were similar between the groups (85.11% and 82.35% in groups A and B, respectively) and similar losses of HBeAg and HBeAg seroconversion rates were achieved. Moreover, for patients with CHB who were HBeAg (-), reductions in HBV DNA were similar. Among all patients with CHB, the rates of normalization of ALT and the loss of HBsAg were similar. The overall incidence of adverse events was comparable between the groups. CONCLUSION: In conclusion, the 48-week administration of Qingzhong showed noninferior efficacy and safety profiles compared to Viread in Chinese patients with CHB.

Anti-Helicobacter pylori compounds from the ethanol extracts of Geranium wilfordii.

UNLABELLED: ETHNOPHARMOCOLOGICAL RELEVANCE: Geranium wilfordii Maxim has been extensively used in Chinese Herbal Medicine for treating gastrointestinal disorders, diarrhea and dysentery. In the current study we aimed to investigate the anti-Helicobacter pylori activity of ethanol extracts of Geranium wilfordii Maxim and its main active compounds, corilagin and 1,2,3,6-tetra-O-galloyl-ß-D-glucose. MATERIALS AND METHODS: The plant materials were extracted three times with ethanol and the concentrated filtrate was successively fractioned into chloroform, ethyl acetate, and n-BuOH-soluble portions which were examined in vitro for the anti-Helicobacter. pylori activity. Employing a standard strain and five clinical isolates of Helicobacter pylori, the extract, fractions and compounds of Geranium wilfordii Maxim were assessed in vitro. RESULTS: The ethanol fraction, ethyl acetate fraction, corilagin, and 1,2,3,6-tetra-O-galloyl-ß-D-glucose were found to be strongly inhibitory to Helicobacter. pylori (MICs: 40, 30, 4, and 8µg/ml respectively). CONCLUSIONS: The results of the present study showed that the ethanol and the ethyl acetate extracts from Geranium wilfordii Maxim displayed as well the most significant inhibition to the growth of Helicobacter. pylori, of which corilagin and 1,2,3,6-tetra-O-galloyl-ß-D-glucose have been identified main anti-Helicobacter pylori active constituents.

[Analysis of a randomized, double-blind, double-dummy, controlled, multicenter study confirmed the similar therapeutic efficacies of entecavir maleate and entecavir for treatment of HBeAg-positive chronic hepatitis B].

OBJECTIVE: To evaluate the efficacy and safety of entecavir maleate (ETV) versus ETV in Chinese patients with hepatitis B e antigen(HBeAg)-positive chronic hepatitis B(CHB). METHODS: The patient population of this previously published randomized, double-blind, double-dummy, controlled, multicenter study was expanded by patients in the 0.5 mg/day ETV maleate group (total n = 110) and patients in the 0.5 mg/day ETV group (total n = 108). At treatment weeks 12, 24 and 48, hepatitis B virus (HBV) DNA levels were measured by the Roche Cobas Ampliprep/Cobas Taqman PCR assay. Adverse events (AE) were recorded. RESULTS: As in the original analysis, the two treatment groups showed similar characteristics at baseline. In addition, the results for the all therapeutic effects showed identical trends to the results obtained in the original analysis, including the statistically similar effects of ETV and ETV maleate treatment-induced decreases in mean HBV DNA level at weeks 12, 24, and 48 (ETV: by 4.28, 5.00, and 5.53 log10 IU/ml vs. ETV maleate: by 4.46, 4.99, and 5.51 log10 IU/ml, respectively; all vs. baseline P more than 0.05), achievement of undetectable levels of serum HBV DNA ( less than 20 IU/ml) at week 48 (ETV: 38.18% vs. ETV maleate: 35.19%; P more than 0.05), HBeAg loss rates at week 48 (ETV: 10.91% vs. ETV maleate: 12.96%; P more than 0.05), HBeAg seroconversion rates at week 48 (ETV: 7.77% vs. ETV maleate: 10.38%; P more than 0.05), normalization of alanine aminotransferase at week 48 (ETV: 75.47% vs. ETV maleate: 82.86%; P more than 0.05), and overall incidence of AE (ETV: 18.02% vs. ETV maleate: 17.43%; P more than 0.05). CONCLUSION: Performing analysis of the therapeutic efficacies of entecavir maleate versus entecavir with a larger study population confirmed our original findings of similar efficacy and safety profiles for these two drugs in patients with HBeAg-positive CHB.

Determination of sinomenine sustained-release capsules in healthy Chinese volunteers by liquid chromatography-tandem mass spectrometry.

A sensitive and selective liquid chromatographic tandem mass spectrometric method was developed and validated for the determination of sinomenine in human plasma. Plasma samples were precipitated using methanol with metronidazole as internal standard. Separation was carried out on an Inertsil ODS-3 column using a mixture of 0.2% ammonium acetate solution (A) and methanol (B) as the mobile phase with linear gradient elution as follows: 0 min (50%B)→1.5 min (80%B)→4.5 min (80%B)→4.6 min (50%B)→6.0 min (50%B). All mass data were obtained in the positive ion mode, and the fragmentation transitions for the selective multiple reaction monitoring were m/z 330→181 and 172→128 for sinomenine and metronidazole, respectively. The method was fully validated to be accurate and precise with a linear range of 0.5-500 ng/mL and applied to a single- and multiple-dose pharmacokinetics study of sustained-release capsules of sinomenine hydrochloride in 20 healthy Chinese volunteers. After oral administration of a single 60-mg dose, the T(max), C(max), AUC(0-96) and t(1/2) were 7.9±2.0h, 123±22 ng/mL, 3032±682 ng h/mL and 13.4±1.6 h, respectively. After oral administration of the 60 mg capsules twice-daily for 7 consecutive days, these parameters were 4.4±3.6 h, 279±69 ng/mL, 7333±2096 ng h/mL and 15.1±1.3 h, respectively. The AUC and C(max) values after multiple-dose treatment were significantly higher than those after a single-dose treatment (P<0.01), with an accumulation factor of 2.49±0.77.

[Analysis of spontaneous decline of HBV DNA in chronic hepatitis B patients in 12 weeks].

OBJECTIVE: To analyze the spontaneous decline of HBV DNA in chronic hepatitis B patients in 12 weeks. METHODS: Chronic hepatitis B patients not receiving antiviral treatment from 2003 to 2005 were divided into two groups according to the baseline value of ALT and TBil. Spontaneous decline of HBV DNA were retrospected, and the influence of the baseline value of ALT and TBil on spontaneous decline of HBV DNA was analyzed. RESULTS: Total of 213 chronic hepatitis B patients (male 174, female 39, aged from 18 to 65) were recruited in this study, including 124 mild and moderate type of hepatitis B, 89 severe type of hepatitis B, and 19 patients (8.92%) were lost at the end of the 12th week. The mean baseline value of HBV DNA of all the patients was (6.66+/-1.03) log10 copies/ml, at 12 week the mean value of HBV DNA of all the patients was (5.98+/-1.53) log10 copies/ml (compared to baseline P<0.01), the decline value of HBV DNA was (0.68+/-1.46) log10 copies/ml. The mean baseline value of HBV DNA of patients with the severe type of hepatitis B was lower than that with the mild or moderate type of hepatitis B patients [(6.45+/-0.99) log10 copies/ml and (6.81+/-1.04) log10 copies/ml respectively] (P<0.05). However, there was no significant difference in the mean and the declined value of HBV DNA between these two groups at the 12th week (P<0.05). At the 12th week, the baseline values of ALT and TBil were higher in patients with HBV DNA3 log10 copies/ml (P>0.05); And there were no significant difference in the baseline values of ALT and TBil between patients with the declined value of HBV DNA>or=2 log10 copies/ml and patients with declined value of HBV DNA less than 2 log10 copies/ml. At the 12th week, the mean and the declined value of HBV DNA were similar between the patients with ALT5xULN at baseline. The mean baseline value of HBV DNA of patients in the group of patients whose baseline value of ALT5xULN while TBil>5xULN, ALT5xULN, ALT>5xULN while TBil0.05 respectively). CONCLUSIONS: There is spontaneous decline of HBV DNA in patients with chronic hepatitis B in 12 weeks, but the level of liver injury is not correlated with the level of spontaneous decline of HBV DNA in chronic hepatitis B patients in 12 weeks.

[Effect of magnesium isoglycyrrhizinate on the proliferation and oxidative stress of rat hepatic stellate cells in vitro].

OBJECTIVES: To investigate the effect of magnesium isoglycyrrhizinate on the proliferation and oxidative stress of rat hepatic stellate cells (HSCs). METHODS: The effect of various concentrations of maganesium isoglycyrrhizinate on the proliferation of primary rat HSCs and HSCs strains were measured by making cell growth curves and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphennylterazolium bromide (MTT) colorimetric assay. Morphological changes of the rat HSCs were also studied. After rat HSCs were incubated with various concentrations of maganesium isoglycyrrhizinate and ferric nitrilotriacetate (Fe-NTA) for 24 hours, the activity of superoxide dismutase (SOD) and contents of malondialdehyde (MDA) in supernates were measured to observe the effect of magnesium isoglycyrrhizinate on the oxidative stress of rat HSCs. RESULTS: Compared with the control group, the proliferation of rat HSCs was significantly inhibited when the concentration of magnesium isoglycyrrhizinate in the medium reached a certain level range. In the oxidative stress induced by Fe-NTA, magnesium isoglycyrrhizinate, within a certain strength range, obviously enhanced the activity of SOD and decreased the contents of MDA in supernates of rat HSCs culture media. CONCLUSIONS: Magnesium isoglycyrrhizinate could significantly inhibit the proliferation of rat HSCs and it, within a certain strength range, exert protective effects in the oxidative stress induced by Fe-NTA.