Adenine ; analogs & derivatives ; pharmacology ; Drug Resistance, Viral ; Hepatitis B virus ; drug effects ; Humans ; Organophosphonates ; pharmacology

OBJECTIVE: To explore the effects of oral exposure to titanium dioxide nanoparticles (TiO₂ NPs) on the composition and structure of human gut microbiota. METHODS: The particle size, shape, crystal shape and degree of agglomeration in ultrapure water of TiO₂ NPs were characterized. The in vitro human digestive tract microecological simulation system was established by simulating the fluid environment and physical conditions of stomach, small intestine and colon, and the stability of the simulation system was evaluated. The bacterial communities were extracted from human feces and cultured stably in the simulated system. They were exposed to 0, 20, 100 and 500 mg/L TiO₂ NPs, respectively, and the bacterial fluids were collected after 24 h of exposure. The effect of TiO₂ NPs on the composition and structure of human gut microbiota was analyzed by 16S rRNA sequencing technology. Linear discriminant analysis effect size (LEfSe) was used to screen differential bacteria, and the Kyoto encyclopedia of genes and genomes (KEGG) database for functional prediction. RESULTS: The spherical and anatase TiO₂ NPs were (25.12±5.64) nm in particle size, while in ultra-pure water hydrated particle size was (609.43±60.35) nm and Zeta potential was (-8.33±0.22) mV. The in vitro digestive tract microecology simulation system reached a relatively stable state after 24 hours, and the counts of Enterococci, Enterobacte-rium, and Lactobacillus reached (1.6±0.85)×10⁷, (5.6±0.82)×10⁷ and (2.7±1.32)×10⁷, respectively. 16S rRNA sequencing results showed that compared with the control group, the number and evenness of gut microbiota were not significantly affected at phylum, class, order, family and genus levels in TiO₂ NPs groups (20, 100 and 500 mg/L). The relative abundance of some species was significantly changed, and a total of 42 different bacteria were screened between the TiO₂ NPs groups (20, 100 and 500 mg/L) and the control group [linear discriminant analysis(LDA) score>3], represented by Enterobacter, Bacteroidaceae, Lactobacillaceae, Bifidobacteriaceae and Clostridium. Further predictive analysis of gut microbiota function showed that TiO₂ NPs might affect oxidative phosphorylation, energy meta-bolism, phosphonate and phosphonate metabolism, and methane metabolism (P < 0.05). CONCLUSION In human digestive tract microecological simulation system, TiO₂ NPs could significantly change the composition and structure of human gut microbiota, represented by Enterobacter and probiotics, and may further affect a variety of metabolism and function of the body.
Bacteria/genetics* ; Gastrointestinal Microbiome ; Gastrointestinal Tract ; Humans ; Nanoparticles ; Organophosphonates/pharmacology* ; RNA, Ribosomal, 16S ; Titanium/pharmacology* ; Water/pharmacology*

According to the super-position principle of the reinforcement of biological activities, a series of novel E-substituted 2, 3-diaryl propenoic acyloxy phosphonate derivatives were designed and synthesized. And the structures of the target compounds were confirmed by IR, 1H NMR, 13C NMR and elemental analysis. Furthermore, the cytotoxicities of all compounds on A-549, SGC-7901 and EC-109 in vitro were evaluated by MTT assay, and some of them showed good antitumor activity. Among the active compounds, especially, the IC50 value of compound 3e was (12.7 ± 1.9) μmol x L(-1) against A-549 cells, similar to cisplatin [IC50 = (8.0 ± 1.5) μmol x L(-1)], compounds 3g and 3k had better inhibition effect on EC-109 cells growth, with the IC50 values of (9.5 ± 1.8) μmol x L(-1) and (11.5 ± 0.9) μmol x L(-1) respectively, and compounds 3i and 3k exhibited good cytotoxic property on A-549, SGC-7901 and EC-109, which were worth further investigation.
Antineoplastic Agents ; chemical synthesis ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; Drug Design ; Humans ; Organophosphonates ; chemical synthesis ; pharmacology

Adefovir dipivoxil (ADV) is a nucleotide anti-hepatitis B virus drug, which is able to effectively repress the replication of hepatitis B virus (HBV). ADV is a reverse transcriptase inhibitor. However, with the prolonged period of using, many kinds of HBV genetic mutants will occur and therefore resistance to ADV will be created. The purpose of this review is to draw the attention to the molecular mechanism of resistance to ADV.
Adenine ; analogs & derivatives ; pharmacology ; Animals ; Antiviral Agents ; pharmacology ; Drug Resistance ; genetics ; Hepatitis B virus ; drug effects ; genetics ; Humans ; Mutation ; Organophosphonates ; pharmacology ; Reverse Transcriptase Inhibitors ; pharmacology

Adenine ; analogs & derivatives ; pharmacology ; Drug Resistance, Viral ; genetics ; Genome, Viral ; Hepatitis B virus ; drug effects ; genetics ; Organophosphonates ; pharmacology ; Plasmids ; Viral Proteins ; genetics

OBJECTIVETo study the factors influencing the long-term usage of lamivudine (LAM) in chronic hepatitis B (CHB) patients and the management after drug-resistance.

METHODS383 cases of naive CHB patients in our outpatient clinic were treated with lamivudine (100 mg/d) and followed up for at least over 1 year from 2001 to 2010. 129 cases encountered lamivudine-resistance and were then divided into two groups: patients in group A were switched to adefovir dipivoxil (ADV) alternative treatment and those patients in group B were added with ADV for continuous treatment. Efficacy assessment factors included serum HBV markers, HBV DNA, ALT, AFP and other biochemical indicators.

RESULTSAmong the 383 cases, patients with HBV DNA negative conversion (PCR below test line) at 3 months, 6 months, 1 year, 2 years, 3 years and > 3 years after initial treatment were respectively 156 cases (40.7%), 213 cases (55.6%), 228 cases (59.5% ), 217cases (56.7%), 214 cases (55.9%) and 213 cases (55.6%). HBeAg/HBeAb seroconversion occurred in 62 cases (22.6%). 12 cases were found with primary LAM resistance, 129 cases with HBV breakthrough and rebound, the cumulative resistance rate was 36.8% and the cumulative rebound rate was 34.8%. High baseline viral load, baseline ALT levels < 2 ULN, Lower virologic response rate at week 24 were associated with a higher rebound rate (chi2 is 35.716, 8.728, 43.534, respectively, all with P < 0.01).Viral breakthrough and rebound occurred in 112 patients (86.8%) within 1 year and a half, 123 patients (95.3%) occurred at the end of 2 years and no patient with viral breakthrough and rebound after 5 years. For the patients with viral rebound in group A and group B, the rates of HBV DNA loss were 22.7% (15/66) and 58.7% (37/63) respectively, and the viral response rates were 59.1% (39/66) and 87.3% (52/63) respectively, with chi2 values equaled 17.364 and 12.975 respectively (P < 0.01).

CONCLUSIONFor the chronic hepatitis B patients on initial treatment with lamivudine, the viral rebound occurred mainly within 2 years. LAM combined with ADV is more effective than ADV alone for lamivudine-resistant patients.

Adenine ; analogs & derivatives ; pharmacology ; therapeutic use ; Adolescent ; Adult ; Aged ; Antiviral Agents ; pharmacology ; therapeutic use ; Drug Resistance, Viral ; Female ; Follow-Up Studies ; Hepatitis B, Chronic ; drug therapy ; Humans ; Lamivudine ; pharmacology ; therapeutic use ; Male ; Middle Aged ; Organophosphonates ; pharmacology ; therapeutic use ; Young Adult

To design and synthesis a series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates with more potent anti-HBV activity, adefovir dipivoxil was used as lead compound, according to the results of enhanced oral bioavailability and antiviral activities of nucleoside L-amino acid ester prodrugs. Eleven novel L-amino acid ester prodrugs of acyclic nucleoside phosphonates were designed and synthesized, their anti-HBV activities were evaluated in HepG2 2.2.15 cells. Eight compounds exhibited antiviral activity, and compound 11 showed the most potent anti-HBV activity and highest selective index in vitro (EC50 0.0952 micromol x L(-1), SI 69523). Moreover, by analyzing the primary structure and activity relationship of these compounds, it could be suggested that L-amino acid ester strategy has significant potential in the acyclic nucleoside phosphonates prodrug design.
Amino Acids ; chemistry ; Antiviral Agents ; chemical synthesis ; pharmacology ; Cell Line, Tumor ; Hepatitis B virus ; drug effects ; Humans ; Liver Neoplasms ; pathology ; virology ; Nucleosides ; chemical synthesis ; pharmacology ; Organophosphonates ; chemical synthesis ; pharmacology ; Prodrugs ; chemical synthesis ; pharmacology

AIMTo search for some substituted alpha-amino phosphonates as leading compounds with the vasodilator effects.

METHODSTarget compounds were prepared from benzyl aldehyde, piperazine and diethyl phosphite using alcohol as solvent via Mannich-type reaction. In isolated rat aorta and in isolated guinea pig ileum, the vasodilator effects of compounds were investigated and evaluated whether they activated muscarine receptor.

RESULTSSeven compounds of substituted alpha-amino phosphonates have been synthesized and identified by IR, 1H NMR and elemental analysis. Three of them, compound 2a, 2b and 2c have vasodilator activity and do not activate M receptor.

CONCLUSIONTwo (2b and 2c) of them were found to have the notable vasodilator effect, and the rates of relaxing are (67 +/- 21) % and (82 +/- 18)%, separately. But they did not activate M receptors on ileum.

Animals ; Aorta ; drug effects ; Benzylamines ; chemical synthesis ; chemistry ; pharmacology ; Guinea Pigs ; Ileum ; drug effects ; Molecular Structure ; Muscle Contraction ; drug effects ; Organophosphonates ; chemical synthesis ; chemistry ; pharmacology ; Rats ; Vasodilation ; drug effects ; Vasodilator Agents ; chemical synthesis ; chemistry ; pharmacology

OBJECTIVETo analyze the prognosis of hepatitis B virus (HBV) recurrence after liver transplantation.

METHODSThirty-eight patients (37 males; 1 female) with HBV-related end-stage liver disease underwent liver transplantation at our institute between December 1998 and November 2009 and experienced HBV recurrence. Clinical data from pre-transplant and follow-up examinations were retrospectively retrieved from medical records, and included serologic indices of HBV (HBV DNA, markers of liver function) and histological findings from liver biopsy.

RESULTSThe median follow-up time was 45.1 months. The median time to HBV recurrence after transplantation was 31.8 months (range: 0.3 to 72.8 months) for histologically benign cases and 13.7 months (range: 0.3 to 66.6 months) for malignant cases. HBV DNA gene mutations were detected in 21% (8/38) of cases. Eighteen patients were treated with entecavir or adefovir, with respect to gene mutations, and HBV DNA fell below 103 copies/ml and liver function became normal. Twenty-two patients died, and causes of death included hepatocellular carcinoma (HCC, n=18), organ failure (n=2), or infection (n=1).

CONCLUSIONHBV gene mutations and HCC recurrence were important risk factors for HBV recurrence in our study population. In addition, patients with benign liver diseases who received salvage therapy with adefovir or entecavir achieved a satisfactory prognosis.

Adenine ; analogs & derivatives ; pharmacology ; Adult ; Female ; Hepatitis B ; diagnosis ; virology ; Hepatitis B virus ; drug effects ; genetics ; Humans ; Lamivudine ; pharmacology ; Liver Transplantation ; adverse effects ; Male ; Middle Aged ; Organophosphonates ; pharmacology ; Prognosis ; Recurrence ; Retrospective Studies

This study was aimed to research the changes of the biological characteristics of Hepatitis B virus-resistant mutant model in vivo. The anti-ADV mutant HBV plasmid of rtA181V and rtN236T, prepared by Multi Site-Directed Mutagenesis Kit, was transferred into mice via the tail vein, and the levels of HBV-DNA replication were detected after Anti-HBV drugs treatment. The HBV-DNA replication had been detected in the mutant mice, which means that the establishment of HBV-resistance mutant model in vivo was successful, but the level of HBV DNA replication intermediates in the anti-ADV mutant mice liver were decreased compared with wild 4.1kb HBV plasmid mice. The wild-type mice were sensitive to Lamivudine, Adefovir dipivoxil and Entecavir. Though the mutant mice were also sensitive to Entecavir, the sensitivity to lamivudine and Adefovir dipivoxil decreased. As a result, this study established the Adefovir-resistant hepatitis B virus mouse model successfully. However, the replication level of HBV-DNA was reduced in this model, and Adefovir dipivoxil in the mutant mice had no significant inhibition effect on HBV-DNA.
Adenine ; analogs & derivatives ; pharmacology ; Animals ; Antiviral Agents ; pharmacology ; Base Sequence ; Drug Resistance, Viral ; genetics ; Hepatitis B ; drug therapy ; virology ; Hepatitis B virus ; drug effects ; genetics ; Male ; Mice ; Mice, Inbred BALB C ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Mutation ; Organophosphonates ; pharmacology