Adefovir Dipivoxil plus Chinese Medicine in HBeAg-Positive Chronic Hepatitis B Patients: A Randomized Controlled 48-Week Trial / 中国结合医学杂志

OBJECTIVE@#To evaluate the effects of a 48-week course of adefovir dipivoxil (ADV) plus Chinese medicine (CM) therapy, namely Tiaogan Jianpi Hexue () and Tiaogan Jiedu Huashi () fomulae, in hepatitis B e antigen (HBeAg)-positive Chinese patients.@*METHODS@#A total of 605 HBeAg-positive Chinese CHB patients were screened and 590 eligible participants were randomly assigned to 2 groups in 1:1 ratio including experimental group (EG, received ADV plus CM) and control group (CG, received ADV plus CM-placebo) for 48 weeks. The major study outcomes were the rates of HBeAg and HBV-DNA loss on week 12, 24, 36, 48, respectively. Secondary endpoints including liver functions (enzymes and bilirubin readings) were evaluated every 4 weeks at the beginning of week 24, 36, and 48. Routine blood, urine, and stool analyses in addition to electrocardiogram and abdominal B scan were monitored as safety evaluations. Adverse events (AEs) were documented.@*RESULTS@#The combination therapy demonstrated superior HBeAg loss at 48 weeks, without additional AEs. The full analysis population was 560 and 280 in each group. In the EG, population achieved HBeAg loss on week 12, 24, 36, and 48 were 25 (8.90%), 34 (12.14%), 52 (18.57%), and 83 (29.64%), respectively; the equivalent numbers in the CG were 20 (7.14%), 41 (14.64%), 54 (19.29%), and 50 (17.86%), respectively. There was a statistically significant difference between these group values on week 48 (P<0.01). No additional AEs were found in EG. Subgroup analysis suggested different outcomes among treatment patterns.@*CONCLUSION@#Combination of CM and ADV therapy demonstrated superior HBeAg clearance compared with ADV monotherapy. The finding indicates that this combination therapy may provide an improved therapeutic effect and safety profile (ChiCTR-TRC-11001263).

Study on Pharmacokinetics of Metabolites of Adefovir in Rats after Intragastric Administration of Adefovir Derivatives / 中国药房

OBJECTIVE： To establish a method for the determination of adefovir （PMEA） and study the pharmacokinetics of metabolites PMEA in rats after intragastric administration of PMEA derivatives [PMEA prodrug， adefovir-ursodeoxycholic acid-3-propyl ester， L-leucine-3-propyl ester （PMEA-1c）] in rats. METHODS： HPLC-MS/MS method was adopted. The determination was performed on BEH C18 column with mobile phase consisted of 0.1％ formic acid acetonitrile-0.1％ formic acid water （gradient elution） at the flow rate of 0.25 mL/min. The column temperature was 30 ℃， and sample size was 1 μL. The quantitative ions were PMEA m/z 274.1→162.1， puerarin （internal standard） m/z 417.1→267.1. 12 rats were randomly divided into adefovir dipivoxil （ADV） group （positive control， 90 mg/kg） and PMEA-1c group （160 mg/kg）， with 6 rats in each group. They were given relevant medicine once intragstrically， and the blood samples were collected from tail vein 0.083， 0.25， 0.5， 0.75， 1， 2， 4， 6， 8， 10， 12， 24 h after administration to determine the plasma concentration of PMEA. Relevant pharmacokinetic parameters were calculated by using DAS 2.0 software. RESULTS： The linear range of PMEA was 6.1-440.0 ng/mL （r＝0.998 5）. RSDs of intra and inter day of precision and stability tests were all less than 10％ （n＝3， 5， 6）， and the accuracy was 82.16％-97.33％ （RSD≤6.4％， n＝5）. Matrix effects ranged from 95.96％-106.35％ （RSD≤4.9％， n＝5）. The pharmacokinetic parameters of PMEA in ADV group and PMEA-1c group were as follows as t1/2 were （1.762±0.117） and （2.548±0.174） h； AUC0-24 h were （2 170.059±146.091） and （4 704.257±176.792） μg·h/L； cmax were （613.092±9.504） and （697.295±15.275） μg/L， respectively. Compared with ADV group， t1/2， AUC0-24 h， AUC0-∞ and cmax of rats in PMEA-1c group were increased significantly （P＜0.01 or P＜0.001）. CONCLUSIONS： Established method is accurate and reliable. The trial indicates that PMEA-1c metabolism is single compartment model， show that can be used as a potential prodrug for adefovir， which lay a foundation for the further study of adefovir prodrug.

Lamivudine plus tenofovir versus lamivudine plus adefovir for the treatment of hepatitis B virus in HIV-coinfected patients, starting antiretroviral therapy

Background: Combination of tenofovir disoproxil fumarate (TDF), lamivudine (3TC) and efavirenz (EFV) is preferred in the treatment of HIV/hepatitis B virus (HBV) coinfection. We postulated that a HBV active nucleoside reverse transcriptase (RT) inhibitor/nucleotide RT inhibitor backbone of adefovir dipivoxil (ADV) +3TC would be as effective as TDF +3TC for the Indian population. Objective: ADV + 3TC could be an alternative option for these HIV/HBV coinfected individuals, preserving the dually active TDF + 3TC as second-line nucleoside backbone following failure of the first-line ART. Materials and Methods: This randomised control trial (CTRI/2012/03/002471) was carried out at the ART Centre of Calcutta School of Tropical Medicine, India. Seventy-eight (39 on each arm) treatment-naïve HIV/HBV coinfected patients were randomised to receive either the combination of lamivudine + tenofovir + EFV or lamivudine + adefovir + zidovudine + EFV and followed up for 120 weeks. Results: Median age of the study participants was 36 years (21–62), majority were male (61/78; 78.2%) and heterosexually (39/78; 50%) infected. Baseline characteristics were identical in both arms. There was no statistically significant difference in median aspartate aminotransferase (37 vs. 29.5 U/L), alanine aminotransferase (ALT) (36 vs. 34.5 U/L), ALT normalisation rate (80 vs. 70%), AST to platelet ratio index (0.45 vs. 0.33), CD4 count (508 vs. 427 cells/mm3), HBV DNA suppression (81.8 vs. 70%), hepatitis B e antigen loss (9 vs. 5%), hepatitis B surface antigen seroclearance rate (6.06 vs. 18.75%) and death (3 vs. 3) at 120 weeks between TDF (n = 33) and ADV (n = 32), respectively. Conclusions: Adefovir plus lamivudine is an effective alternative of tenofovir plus lamivudine in long-term HBV treatment outcome in HIV/HBV coinfected patients.

Adefovir-induced Fanconi syndrome associated with osteomalacia

Fanconi syndrome is a dysfunction of the proximal renal tubules that results in impaired reabsorption and increased urinary loss of phosphate and other solutes. The pathophysiology of drug-induced Fanconi syndrome is unclear. Here we report the case of a 36-year-old woman who presented with pain in multiple bones and proteinuria. She had a 7-year history of taking adefovir at 10 mg/day for chronic hepatitis B. Three years previously she had received surgery for a nontraumatic right femur neck fracture, after which she continued to complain of pain in multiple bones, and proteinuria, glycosuria, and phosphaturia were noted. The findings of a light-microscope examination of a renal biopsy sample were normal, but mitochondrial damage of the proximal tubules was evident in electron microscopy. Western blot analysis revealed that the level of serum fibroblast growth factor 23 (FGF23) was lower than in normal controls. After 2 months of treatment, hypophosphatemia and proximal tubular dysfunction were reversed, and serum FGF23 had normalized. This case suggests that direct mitochondrial damage in proximal tubules can cause drug-induced Fanconi syndrome associated with osteomalacia.

Systematic evaluation of Compound Biejia Ruangan Tablets combined with Adefovir Dipivoxil in treatment of chronic hepatitis B with liver fibrosis / 中草药

To evaluate the clinical curative effect of Compound Biejia Ruangan Tablets (CBRT) combined with Adefovir Dipivoxil in the treatment of chronic hepatitis B with liver fibrosis using Meta-analysis. Cochrane library, PubMed, CNKI, Wanfang databases, and VIP were retrieved comprehensively to collect randomized controlled trials (RCTs) of CBRT combined with Adefovir Dipivoxil in the treatment of chronic hepatitis B with hepatic fibrosis from their inception to October 2017. treatment group was treated with CBRT combined with Adefovir Dipivoxil, and the control group was treated with Adefovir Dipivoxil. All the data were analyzed using Revman 5.3. A total of 19 RCTs and 1 776 patients were included. Meta-analysis results showed that the serum indexes including HA, IV-C, LN, PCIII, ALT, AST, and TBIL of the treatment group, were significantly lower than those of control group. HA [SMD = -1.72, 95% CI (-2.26, -1.17), P = 0.000 01]; IV-C [SMD = -1.10, 95% CI (-1.66, -0.54), P = 0.000 10]; LN [SMD = -1.18, 95% CI (-1.64, -0.73), P = 0.000 01]; PCIII [SMD = -1.52, 95% CI (-1.97, -1.07), P = 0.000 01]; ALT [SMD =-0.48, 95% CI (-0.68, -0.28), P = 0.000 01]; AST [SMD = -1.19, 95% CI (-2.08, -0.29), P = 0.010 00]; TBIL [SMD = -0.98, 95%CI (-1.38, -0.58), P = 0.000 01]; There were no significant difference in serum HBV DNA, and HbeAg negative conversion rate treatment group compared with control group. HBV DNA [RR = 1.21, 95% CI (0.97, 1.50), P = 0.09]; HBeAg [RR = 1.05, 95% CI (0.82, 1.34), P = 0.70]; The total clinical effective treatment group was significantly better than control group. [RR = 1.25, 95% CI (1.15, 1.36), P = 0.000 01]. Compared with the single use of Adefovir Dipivoxil, the clinical curative effect of CBRT combined with Adefovir Dipivoxil in the treatment of chronic hepatitis B with liver fibrosis is better,which can significantly reduce the level of serum liver fiber markers and improve liver function in patients with biochemical indicators and the total clinical efficiency.

In vitro metabolism and stability of adefovir mixed phosphonate derivative Q3-I2 / 中国药科大学学报

@#A, UPLC-QTOF-MS/MS and UPLC-MS/MS were used to investigate the derivative of adefovir mixed phosphonate Q3-I2. Stability and in vitro metabolites of Q3-I2, and the control drug adefovir dipivoxil were co-inculbated with artificial gastric juice, artificial intestinal juice, rat blank plasma and rat liver microsomes, using UPLC-MS/MS and UPLC-QTOF-MS/MS measure the residual concentration of the compounds in each incubation system and the metabolites in the liver microsomal system, respectively, and calculate the half-life and clearance rate by the substrate elimination method. The compounds designed and synthesized in this experiment are stable in the gastrointestinal tract, prolonging t1/2 of plasma and liver microsomes and rapidly degrading the active meta-bolites. In the liver microsomal system, a total of 8 metabolites were detected by positive and negative ion mode, including hydrolysis, oxidation, acetylation, and glucuronidation.

Compare the effect of combined therapy between telbivudine plus adefovir dipivoxil and lamivudine plus adefovir dipivoxil corresponding to renal function in patients with hepatitis B virus infection / 中华肝脏病杂志

Objective@#To compare the effect of combined therapy using lamivudine (LAM) plus adefovir (ADV) versus telbivudine (LdT) plus adefovir corresponding to the renal function of CHB patients.@*Methods@#A total of 120 patients with chronic hepatitis B were enrolled. According to single daily dosing, they were divided into 4 groups: LdT + ADV group (n = 32), ADV+LdT group (n = 28), LAM + ADV group (n = 38) and ADV + LAM group (n = 22). Hepatorenal function, HBV serological markers, HBV DNA quantification, creatine kinase (CK) and other parameters were examined every 3 months. Serum alanine aminotransferase (ALT) normalization rate, undetectable HBV DNA rate, hepatitis B e antigen (HBeAg) seroconversion rate, level of serum creatinine (CR) and estimated glomerular filtration rate (eGFR) were analyzed at baseline time, and at weeks 24 and 52.Stastical data were analyzed by t- test and analysis of variance, count data using χ 2 test.@*Results@#There was no statistically significant difference between the four groups in terms of ALT normalization rate, HBeAg seroconversion rate, undetectable HBV DNA rate at 24 and 52 weeks. Compared with baseline, at 24 weeks of treatment, there was no significant change in serum creatinine and eGFR in the 4 groups, but after 52 weeks of treatment, serum creatinine decreased in LdT + ADV and ADV + LdT groups and eGFR increased (P < 0.05); Serum creatinine in ADV and ADV + LAM increased, and eGFR was decreased than before (P < 0.05). After treatment, there was no significant difference in renal function between the four groups at 24 weeks, but at week 52, eGFR increased and serum creatinine decreased in LdT + ADV group compared with LAM + ADV group (P < 0.05); ADV + LdT Compared with ADV + LAM group, eGFR increased and serum creatinine decreased (P < 0.05). At 52 weeks of treatment, 5 patients with mildly impaired renal function in the ADV + LdT group [n = 10, eGFR 60-90 ml·min-1 ·(1.73 m2)-1] returned to normal, and none of the ADV + LAM group (n = 9) returned to normal.@*Conclusion@#For patients with mild impaired renal function, adding LdT combined with ADV can improve renal function compared to that of LAM plus ADV.

Enhanced dissolution and intestinal absorption of adefovir dipivoxil by cocrystal formation with acetaminophen / 药学学报

In current study, adefovir dipivoxil (AD)-acetaminophen (AP) cocrystal (molar ratio, 1:1) was prepared by slow evaporation from acetonitrile, followed by physicochemical characterizations using differential scanning calorimetry, powder X-Ray diffraction and Fourier transform infrared spectroscopy. Molecular modeling showed that the phosphoester group of AD was connected with the amide group of AP through hydrogen bonds. In comparison to crystalline AD, the solubility and dissolution rate of AD from AD-AP cocrystal were significantly enhanced by 1.5-fold and 1.6-fold, respectively. In addition, based on the rat single-pass intestinal perfusion study, the permeabilities of AD in various intestinal sections (i.e., duodenum, jejunum, ileum and colon) were significantly improved (e.g., about 3-fold enhancement in duodenum) after cocrystallization with AP by inhibiting P-glyprotein mediated efflux of AD, which will benefit absorption in vivo and subsequent oral bioavailability of poorly permeable drug AD.

Synthesis and bioactivity of mixed phosphonate derivatives of adefovir with hepatic targeting property / 中国药科大学学报

In order to search for new adefovir analogues as anti-HBV agents with enhanced antiviral activity and hepatotrophic property,adefovir bis L-amino acid ester was used as lead compound to produce ten adefovir mono L-(thio)amino acid ester, mono bile acid ester derivatives(6a-6j). The design based on bile acid prodrug strategy,which can improve drug oral bioavaliability and liver-targeted enrichment by using enterohepatic circula-tion of bile acid.Sub-structure combination method was adopted to introduce L-(thio)amino acid ester and bile acid ester fragments on the phosphonate functionality of adefovir. The structures of target compounds were confirmed by 1H NMR, 13C NMR,ESI-MS and ESI-HRMS.HepG 2.2.15 cell were used for in vitro anti-HBV activity assessment.Compound 6c with high antiviral activity(EC500.92μmol/L,SI 512.63)was further investi-gated for its tissue distribution in mice.The results showed that content of compound 6c in liver was higher than that of adefovir dipivoxil,and in contrast its content in kidney was lower than that in positive control at all time points(0.25-12 h).Compound 6c exhibits higher antiviral activity,selective index and higher liver distribution,making it a potential anti HBV agent for further investigation.

Effects of telbivudine and entecavir on improvement of renal function in chronic hepatitis B patients with renal impairment after adefovir dipivoxil treatment / 中国医师进修杂志

Objective To explore the effects of telbivudine (LdT) and entecavir (ETV) on renal function in chronic hepatitis B (CHB) patients with renal damage after adefovir dipivoxil (ADV) treatment. Methods The clinical data of 40 CHB patients with renal damage after ADV treatment from January 2015 to February 2016 were retrospectively analyzed. The patients were divided into 2 groups according to the substitution drugs. Twenty patients in ETV group received ETV replacement therapy, and 20 patients in LdT group received LdT replacement therapy. The serum alanine aminotransferase (ALT), serum creatinine, serum creatine kinase (SCK), urinary β2-microglobulin (Uβ2-MG), estimated glomerular filtration rate (eGFR), classification of renal function, improvement of renal function and positive rate of HBV-DNA were compared between 2 groups. Results There was no statistical difference in serum ALT between 2 group (P＞0.05). The serum creatinine, SCK, Uβ2-MG and eGFR levels after treatment in LdT group were significantly better than those in ETV group: (92.08 ± 9.35) μmol/L vs. (101.21 ± 10.31) μmol/L, (133.69 ± 31.29) U/L vs. (106.14 ± 26.19) U/L, (5 126.17 ± 415.79) μg/L vs. (6 381.92 ± 574.12) μg/L and (81.61 ± 20.52) ml/(min·1.73 m2) vs. (75.34 ± 19.67) ml/(min·1.73 m2), and there were statistical differences (P＜0.05). There was no statistical difference in the positive rate of HBV-DNA after treatment between 2 groups (P＞0.05). The abnormal rate of renal function classification after treatment in LdT group was significantly lower than that in ETV group: 0 vs. 20.0% (4/20), the improvement rate of renal function in ETV group was significantly higher than that in ETV group: 100.0% (20/20) vs. 80.0% (16/20), and there were statistical differences (P＜0.05). Conclusions The effect of LdT on renal function improvement in CHB patients with renal damage after ADV treatment is more obvious than that of ETV, which can significantly improve serum creatinine, SCK, Uβ2-MG and eGFR, and reduce the abnormal renal function.

Hypophosphatemic osteomalacia caused by adefovir dipivoxil: case report and literature review / 中华全科医师杂志

A 61-years male patients with chronic hepatitis B developed hypophosphatemic osteomalacia following long-term use of adefovir dipivoxil in our hospital.With "adefovir dipivoxil" and "osteomalacia" as the search terms,we searched Wanfang database and Chinese Biomedical bibliographic database since 2005,and retrieved 79 cases of adefovir dipivoxil-induced hypophosphatemic osteomalacia.Of the 80 cases,there were 63 males and 17 females with a mean age of (52 ± 11) years.The average duration of disease to first diagnosis made was 17 months,the average duration of adefovir dipivoxil administration to the onset of the disease was 62 months,and the average duration of hepatitis B was 11 years.The most common clinical manifestation was progressive bone pain in all parts of the body (80/80 cases);the most common laboratory finding was decreased serum phosphorus (80/80 cases),followed by abnormal urine tests (55/56 cases) including increased urinary phosphorus,urinary protein and positive urinary occult blood.The X-ray,CT and MRI showed different degrees of decreased bone density,osteoporosis,and bone fracture in severe patients (76/77 cases).It is suggested that clinicians should pay attention to the renal damage during the treatment of adefovir dipivoxil,and the renal function,electrolyte and bone density should be monitored regularly.

Comparison of efficacy and safety between entecavir versus adefovir dipivoxil in the treatment of HBeAg positive chronic hepatitis B / 中国综合临床

Objective To compare the efficacy and safety of entecavir versus adefovir dipivoxil in the treatment of HBeAg positive chronic hepatitis B ( CHB) . Methods Ninety?six cases with HBeAg positive CHB were divided into ETV group and ADV group according to different medication. In addition to conventional treatment,ETV group received entecavir 0. 5 mg/d,ADV group received adefovir dipivoxil 10 mg/d. HBV DNA negative conversion rate,alanine aminotransferase ( ALT) recurrence rate and HBeAg negative conversion rate in 24 weeks,48 weeks and 96 weeks were compared as well as the adverse reactions and liver function in 96 weeks. Results HBV DNA negative conversion rates in ETV group were significantly higher than those in ADV group in 24 weeks,48 weeks and 96 weeks (24 weeks:64. 6％(31/48) vs. 41. 7％(20/48);48 weeks:83. 3％(40/48) vs. 52. 1％(25/48);96 weeks:97. 9％(47/48) vs. 62. 5％(30/48),χ2 =5. 06,10. 72,18. 96,P<0. 05) . ALT recurrence rates in ETV group were significantly higher than those in ADV group at 24 weeks,48 weeks ( 24weeks:77. 1％( 37/48 ) vs. 54. 2％( 26/48 );48weeks:85. 4％( 40/48 ) vs. 62. 5％( 30/48 ) ,χ2=5. 59,6. 54,P<0. 05). There was no significant difference in ALT complication rate at 96 week(χ2=0. 71,P>0. 05) . There was no significant difference in HBeAg negative conversion rate between the two groups through treatment(χ2=0. 07, 0. 22, 0. 44, P>0. 05 ) . After 96 weeks, ALT in both groups decreased significantly ( t =13. 56,11. 85,P<0. 05) ,while ALT in ETV group was significantly lower than that in ADV group ( ( 31. 8 ±8. 6) U/L vs. (38. 5±7. 5) U/L,t=4. 07,P<0. 05). AST in both groups decreased significantly(t=41. 27, 33. 68,P<0. 05),while AST in ETV group was significantly lower than that in ADV group ( (30. 3±6. 5) U/L vs.(37.6±7.1)U/L,t=5.25,P<0.05).TBIL in both groups decreased significantly(t=28.92,22.23,P<0. 05),while TBIL in ETV group was significantly lower than that in ADV group ( (13. 5±3. 3) μmol/L vs. (18. 7±3. 9) μmol/L,t=7. 05,P<0. 05). GGT in both groups decreased significantly (t=16. 99,13. 97,P<0.05),while GGT in ETV group was significantly lower than that in ADV group ( (35.6±10.4)U/L vs. (59. 7±12. 5)U/L,t=10. 27,P<0. 05). There was no significant difference in adverse reaction between the two groups (χ2=1. 96,P>0. 05) . Conclusion Entecavir has a higher rate of HBV DNA negative conversion rate, ALT recurrence rate and HBeAg negative conversion rate in the treatment of HBeAg positive CHB. It is an ideal antiviral drug.

The curative effect of therapeutic instrument of hepatopathy combined with Reduning injection in the treatment for patient with scarlet fever and hepatic injury / 中国医学装备

Objective: To investigate the curative effect of low-frequency therapeutic instrument of hepatopathy combined with Reduning injection in clinical treatment for patients with scarlet fever and hepatitis injury. Methods: 94 patients with scarlet fever and hepatitis injury were divided into observation group (47 cases) and control group (47cases). Patients of control group received the therapy of Reduning injection combined with tablet of adefovir dipivoxil, while the patients of observation group received the therapy of therapeutic instrument of hepatopathy combined with the therapy of control group. The changes of curative effect, indicator of hepatic fibrosis and response rate between two groups were observed. Results: The total effective rate of the observation group (95.7%) was significantly higher than that of control group (70.2%) (x2=7.283, P<0.05). In observation group, the hepatic fibrosis hyaluronic acid, III type procollagen, IV type collagen and laminin of post-treatment were significant improvement than that of pre-treatment (t=3.42, t=2.83, t=2.74, t=2.52, P<0.05). While in control groups, only the laminin of post-treatment was significant improvement than that of pre-treatment (t=2.15, P<0.05). After treatment, CR, VR, BR and HBeAg of observation group were significant higher than that of control group (x2=5.235, x2=5.623, x2=4.993, x2=6.823, P<0.05). Conclusion: The combination of low-frequency treatment of hepatopathy and Reduning injuection for the treatment of patients with scarlet fever and hepatic injury has significant effect, and it can effectively enhance the conversion rate of HBeAg, and improve liver function of patients. Therefore, it is worthy to be further promoteed in the clinical application.

Observing the influences of liver function and virus outcome with telbivudine combined with adefovir dipivoxil / 中国生化药物杂志

Objective To observe the clinical effects of anti-hepatitis B virus with telbivudine combined with adefovir dipivoxil.Methods 82 cases of patients diagnosed with chronic hepatitis B from January 2014 to February 2016, were randomly divided into two groups, the control group were treated with adefovir ester treatment, the observation group were treated with telbivudine combined with adefovir dipivoxil treatment, patients were followed up and recorded Child-Pugh score, aspartate aminotransferase ALT, total bilirubin TBIL, aspartate aminotransferase AST, albumin ALB, HBV-DNA negative rate, HbeAg seroconversion rate case, the use of statistical methods for data analysis.Results After treatment, the observation group Child-Pugh score, ALT values were(4.01±0.79)points,(37.19±4.82)U/L, were better than the control group(5.46±1.16)points,(61.49±9.78)U/L, and the differences were statistically significant (P<0.05).Observation group after treatment TBIL, AST, ALB, respectively(34.91±5.49)μmol/L,(56.49±5.28)U/L,(45.51±4.24)g/L, were better than the control group(61.62±10.06)μmol/L,(78.64±8.16)U/L,(38.76±3.21)g/L, and the differences were statistically significant (P<0.05).The observation group after treatment for HBV-DNA negative rate and HbeAg seroconversion rate(82.93%, 58.54%)respectively were higher(58.54%, 29.27%), and the difference was significant (P<0.05).Conclusion Telbivudine combined with adefovir dipivoxil anti-HBV effect is good, better than medication alone is worthy of further research and application.

Monitoring of early renal injury in chronic hepatitis B patients with long-term adefovir dipivoxil treatment / 中华临床感染病杂志

Objective To evaluate urinary β2-microglobulin (β2-MG) and retinoid binging protein (RBP) in monitoring of early renal impairment in chronic hepatitis B (CHB) patients with long-term adefovir dipivoxil (ADV) treatment. Methods Three hundred and fifty five with CHB admitted in Shaoxing Municipal Hospital from June 2009 to June 2011 were enrolled in the study, among whom 180 cases study group) were treated with ADV monotherapy (n=100) or ADV + lamivudine (LAM) combination therapy (n=80); and 175 cases (control group) were treated with entecavir (ETV). Serum creatinine, urinary β2-MG, RBP and creatinine were measured and glomerular tration rate (eGFR) was estimated regularly during 5-year follow up. Kaplan-Meier method was used to calculate the cumulative incidence of changes in urinary β2-MG and RBP. Results Five-year follow-up results showed that in study group 2, 6, 10, 14 and 24 cases developed urinary β2-MG abnormality in year 1, 2, 3, 4 and 5 of treatment, respectively; and 2, 7, 11, 16 and 20 cases developed urinary RBP abnormality in year 1, 2, 3, 4 and 5 of treatment, respectively; eGFR decreased 20%-30% from baseline in 20 cases, 30%-50% in 13 cases and >50% in 2 cases. The decrease of eGFR ≥30% in 5 years was significantly correlated with urinary RBP and β2-GM abnormality. However, both serum creatinine and eGFR remained stable during the 5 years of follow-up in control group; only 2 cases developed urinary β2-MG abnormality and 3 cases developed urinary RBP abnormality. Conclusions Urinary RBP and β2-MG are sensitive biomarkers of early renal injury during long-term ADV treatment in CHB patients, and ADV should not be used as first-line treatment for CHB.

Preparation and in vitro Evaluation of Self-microemulsifying Drug Delivery System of Adefovir Dipivoxil / 中国药师

Objective: To prepare and in vitro evaluate the self-microemulsifying drug delivery system (SMEDDS) of adefovir dipivoxil (ADV).Methods: The optimized formula was screened by solubility, compatibility, ternary phase diagram and orthogonal design with the self-emulsifying time and particle size of microemulsion as the indices.The property of self-emulsification and the dissolution in vitro of ADV-SMEDDS were also determined.Results: The optimized SMEDDS was composed of Cremophor EL35 (37.5%), Transcutol HP (37.5%) and PECEOL (25%), and the drug loading was 3%.The ADV-SMEDDS formed stable microemulsion after the dilution by 50-fold amount of water in 24 s, the average particle size was (26.30±0.46) nm, the zeta potential was (-8.96±0.57) mV, and the dissolution was more than 85% in 5 min.Conclusion: The optimized formula of ADV-SMEDDS has significantly enhanced solubility and dissolution of adefovir dipivoxil in vitro.

Efficacy evaluation of 104-week telbivudine therapy in HBeAg-positive chronic hepatitis B / 中国感染与化疗杂志

Objective To evaluate the efficacy of telbivudine in HBeAg-positive chronic hepatitis B (CHB) patients by comparing the efficacy of initial telbivudine therapy in treatment-naive patients with sequential telbivudine therapy in patients with poor response to adefovir.Methods A total of 90 HBeAg-positive CHB patients were assigned to receive sequential telbivudine therapy following poor response to adefovir dipivoxil (n=45),or initial telbivudine therapy in antiviral treatment-naive patients (n=45).All patients were treated with telbivudine 600 mg daily for 104 weeks.The efficacy was evaluated in terms of liver function tests,serum HBV markers,HBV DNA and antiviral drug resistance.Results Telbivudine showed good overall efficacy after treatment for 104 weeks in terms of alanine aminotransferase normalization rate (91.1％),HBV DNA negative conversion rate (80.0％),HBeAg loss rate (57.8％),and HBeAg/HBeAb seroconversion rate (30.0％).The HBV DNA negative conversion rate in initial treatment group was significantly higher than that in sequential treatment group (P＜0.05).However,among the patients with early response,the efficacy did not show significant difference between groups (P＞0.05).The patients with early response showed significantly better efficacy than those without early response,in terms of higher HBV DNA negative conversion rate,higher HBeAg loss rate and HBeAg/ HBeAb seroconversion rate (P＜0.000 1 or P＜0.05),but lower virological breakthrough rate (P＜0.05).Conclusions Telbivudine has shown reliable efficacy in CHB patients.Initial telbivudine therapy is better than sequential therapy in CHB patients with poor response to adefovir.However,for patients with early response to telbivudine,no statistical difference is found between initial and sequential therapy in long-term treatment efficacy (104 weeks).The patients receiving sequential telbivudine therapy should be monitored closely for early antiviral response to optimize treatment.

Clinical Predicting Factors of Adefovir Dipivoxil Therapy in Patients with Chronic Hepatitis B / 医学研究杂志

Objective To analyze the efficacy and the predictive factors of adefovir dipivoxil (ADV) therapy in patients with chronic hepatitis B(CHB).Methods Fifty two CHB patients were recruited in this study.All patients were treated for 52 weeks.Liver function,blood cell amounts and HBV DNA levels were detected at time course.Results At time point of 4 weeks,the serum HBV DNA level in good response group were significantly less than poor response group (2.48 ± 0.45 log10 vs 4.72 ± 0.28 log10,P ＜ 0.05).The decreased log value of HBV DNA in good response group was significantly higher than poor response group (3.31 ± 0.36 vs 1.54 ± 0.44,P ＜0.05).At time point of 12 weeks,the decreased log value of HBV DNA and neutrophil percent in good response group were significantly higher than poor response group [3.31 ± 0.36 vs 1.54 ± 0.44,(58.38 ± 2.08) × 109/L vs (46.90 ± 3.01) × 109/L,P ＜ 0.05],the serum HBV DNA level and red blood cell level in good response group were significantly less than poor response group[0.80 ± 0.27 log10vs4.63 ±0.43 log10,(4.50±0.08) ×1012/L vs (6.01 ±0.13) × 1012/L,P ＜0.05].Conclusion The decreased log value of HBV DNA and red blood cell level of 12weeks are the independently predictive factors for adefovir dipivoxil (ADV) therapy in patients with chronic hepatitis B.

Preparation and Formulation Optimization of Nanostructured Lipid Carriers of Adefovir Dipivoxil / 中国药房

OBJECTIVE:To prepare nanostructured lipid carrier of adefovir dipivoxil(ADV-NLC),and optimize the formula-tion. METHODS:Using stearic acid and glycerin monostearate as solid lipid,oleic acid as liquid lipid,Gemini surfactant and poly-sorbate 80 as emulsifier,sodium dodecyl sulfate (SDS) as stabilizer,solvent dispersion ultrasonic method was used to prepare ADV-NLC. And using particle size,polydispersity index,Zeta potential,encapsulation efficiency as indexes,single factor test was conducted to screen Gemini surfactant-polysorbate 80 ratio,emulsifier dosage(ratio of emulsifier to water phase),drug-lipid ratio, solid-liquid lipid ratio. RESULTS:The formula was as follow as 3% emulsifier (Gemini surfactant-polysorbate 80 ratio of 1:2), 4.5% drug-lipid ratio,solid-liquid lipid ratio of 6:5. The average particle size of the prepared ADV-NLC was(48.83±2.65)nm, polydispersity index<0.3,Zeta potential was(-28.7±1.8)mV,encapsulation efficiency was(77.65±0.03)%(n=3). CONCLU-SIONS:ADV-NLC is successfully prepared,and the formulation is reasonable and feasible.

Clinical Analysis of 11 Cases of Adefovir Dipivoxil-induced Renal Hypophosphatemia and Osteomalacia / 中国药师

Objective: To analyze the clinical characteristics of hypophosphatemic osteomalacia induced by adefovir dipivoxil (ADV) in order to improve the understanding of the disease.Methods: A retrospective analysis was performed according to the medical records of 11 cases of ADV-induced hypophosphatemic osteomalacia.The medical history, laboratory indicators (ALT, AST, ALB, SCr, UA, blood glucose, blood pH, BE), bone metabolic markers (25OHD3, PTH, tP1NP, β-CTX, OC), urine indicators (urine pH, 24h urine Ca, 24h urine P, 24h urine Pro, urine Scr), DXA and skeleton ECT signs of the patients with hypophosphatemic osteomalacia induced by ADV were analyzed, and the symptoms, blood P, AKP level and urine routines were followed up after 1-month withdrawal and in July, 2016, respectively.Results: The mean ADV administration time of the 11 patients was (5.7±1.2) years, and the bone pain time was (2.2±0.6) years.The serum P was (0.45±0.99)mmol·L-1, 24h urine P was (17.9±4.8)mmol, AKP was (248±107)IU·L-1,the concentration threshold of renal phosphate was(0.31±0.10)mmol·L-1.After the one-month withdrawal of ADV, the bone pain in the patients were all relieved, and with the phosphorus supplement, the level of serum phosphorus was increased.In July of 2016, the average withdrawal time of ADV was (18.3±10.7) months, the serum phosphorus significantly increased and AKP significantly decreased when compared with that on the admission and 1 month after the ADV withdrawal (P<0.05), and the serum phosphorus of 2 patients returned to normal with the recovery rate of 20% (2/10).The regression analysis showed that the influencing factors on serum phosphorus on the admission were renal concentration threshold of phosphate and tP1NP (P<0.05);the influencing factor on serum phosphorus on the last follow-up was bone mineral density at the admission (P<0.05).Conclusion: Hypophosphatemic osteomalacia is a potential side effect of ADV, and ADV-induced renal injury is not completely reversible, which should be paid more attention in clinical work.