-
Biochemical and Biophysical Research... Sep 2023The number of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients persists even under nucleos(t)ide analogues (NAs) treatment. Aldo-keto reductase...
The number of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients persists even under nucleos(t)ide analogues (NAs) treatment. Aldo-keto reductase family 1 member B10 (AKR1B10) expression has been reported in advanced chronic liver diseases as well as cancer tissues. We observed an association between related to HCC incidence and serum AKR1B10 by analyzing patients under treatment with NAs. Serum AKR1B10 levels measured by ELISA were higher in HCC cases under NA treatment compared with non-HCC cases and were associated with lamivudine- and adefovir pivoxil-, but not entecavir- or tenofovir alafenamide-treated cases. The latter drugs did not increase AKR1B10 values even in HCC cases, suggesting that they influence the reduction of AKR1B10 in any cases. This analysis was supported by in-vitro examination, which showed reduced AKR1B10 expression by entecavir and tenofovir via immunofluorescence staining. In conclusion there was a relationship between HBV-related HCC incidence and AKR1B10 under nucleos(t)ide analogues, especially in the use of lamivudine and adefovir pivoxil, but entecavir and tenofovir had suppressive effects of AKR1B10.
Topics: Humans; Hepatitis B, Chronic; Liver Neoplasms; Aldo-Keto Reductase Family 1 member B10; Lamivudine; Carcinoma, Hepatocellular; Tenofovir; Antiviral Agents; Aldo-Keto Reductases
PubMed: 37419034
DOI: 10.1016/j.bbrc.2023.06.093 -
ACS Omega Nov 2020Adefovir is regarded as a potential antiviral agent. However, it cannot be considered as a valuable drug candidate due to its high polarity that limits its permeability...
Investigation of the Structure and Dynamics of Antiviral Drug Adefovir Dipivoxil by Site-Specific Spin-Lattice Relaxation Time Measurements and Chemical Shift Anisotropy Tensor Measurements.
Adefovir is regarded as a potential antiviral agent. However, it cannot be considered as a valuable drug candidate due to its high polarity that limits its permeability across the human intestinal mucosa. When the ribose phosphate group of adefovir is replaced by the isopolar phosphonomethyl ether functionality, it neutralizes the negative charge of the drug. This makes the drug lipid-soluble and potent to diffuse across the cell membrane. The prodrug adefovir dipivoxil is regarded as a potent antiviral drug against hepatitis B virus (HBV), human immunodeficiency virus (HIV), Rauscher murine leukemia virus (R-MuLV), murine cytomegalovirus (MCMV), herpes simplex virus (HSV), simian immunodeficiency virus (SIV), and feline immunodeficiency virus (FIV). The correlation between the structure and the dynamics of adefovir dipivoxil is determined by measuring the principal components of chemical shift anisotropy (CSA) tensor, site-specific spin-lattice relaxation time, and molecular correlation time at crystallographically different carbon nuclei sites. The CSA parameters, spin-lattice relaxation time, and molecular correlation time of phosphorous nucleus of the organophosphate group of adefovir dipivoxil molecule are also determined. The spin-lattice relaxation time of carbon nuclei varies from 1 to 107 s. The range of molecular correlation time also varies from 10 to 10 s. These remarkable diversities of motional dynamics of the molecules imply that there exist various motional degrees of freedom within this valuable drug and these motional degrees of freedom are independent of each other, which may be the reason for the biological activities exhibited by the drug. The correlation between structure and dynamics of such an important antiviral drug adefovir dipivoxil can be visualized by these types of extensive spectroscopic measurements, which will enlighten the path of inventing advanced medicine in the pharmaceutical industry, and it will also illuminate the understanding of the structure-activity relationships of antiviral drug.
PubMed: 33225168
DOI: 10.1021/acsomega.0c04205 -
Journal of Oncology 2021The purpose of the study was to investigate the effect of entecavir combined with adefovir dipivoxil on clinical efficacy and TNF- and IL-6 levels in patients with...
OBJECTIVE
The purpose of the study was to investigate the effect of entecavir combined with adefovir dipivoxil on clinical efficacy and TNF- and IL-6 levels in patients with hepatitis B cirrhosis.
METHODS
A total of 100 patients with hepatitis B cirrhosis admitted to our hospital between January 2018 and June 2019 were randomly selected and divided into the control group ( = 50) and experimental group ( = 50) according to the order of admission. Among them, the control group patients were treated with entecavir, while the patients in the experimental group received entecavir combined with adefovir dipivoxil. After that, the effective rate of treatment, the incidence of adverse reactions, liver function indexes, liver fibrosis condition, and TNF- and IL-6 expression levels were all compared between the two groups.
RESULTS
The effective rate of treatment in the experimental group was significantly higher than that in the control group, with statistical significance ( < 0.001); the incidence of adverse reactions of the patients in the experimental group was significantly lower than that in the control group, with statistical significance ( < 0.001); the liver function indexes in the experimental group were significantly better than those in the control group, with statistical significance ( < 0.001); the number of patients with liver fibrosis in the experimental group was significantly less than that in the control group, with statistical significance ( < 0.001); the TNF- and IL-6 expression levels in the experimental group were significantly lower than those in the control group, with statistical significance ( < 0.001).
CONCLUSION
Entecavir combined with adefovir dipivoxil in the treatment of hepatitis B cirrhosis can effectively improve the therapeutic effect and reduce the serum inflammatory factor levels, with high safety, which is worthy of application and popularization.
PubMed: 34484339
DOI: 10.1155/2021/9162346 -
Toxicology Letters Apr 2022Organic anion transporters 1 (OAT1) and OAT3 are responsible for transporting adefovir (ADV) into renal tubular epithelial cells. Our previous research found that ADV...
Organic anion transporters 1 (OAT1) and OAT3 are responsible for transporting adefovir (ADV) into renal tubular epithelial cells. Our previous research found that ADV accumulated in the renal interstitium and caused renal interstitial fibrosis when Oat1/3 were inhibited by OATs inhibitor probenecid for long-term. Mast cells (MCs) in the interstitial space are considered to be key drivers of renal fibrosis. The current work investigated the effect of ADV on MCs in vitro and during the development of interstitial fibrosis in rats. Results indicate that ADV triggers chymase release from cultured RBL-2H3 mast cells in a time-and concentration-dependent manner. Angiotensin II (Ang II) in renal interstitium is generated mainly by chymase, renin and other products released from MCs, and has a direct effect on fibrosis through the angiotensin receptor. The concentrations of Ang II and fibrosis was significantly increased after administration of ADV alone or with probenecid for 4 weeks. The MCs membrane stabilizer sodium cromoglycate (SCG) and the angiotensin receptor antagonist Valsartan (VAL) could ameliorate ADV-induced nephrotoxicity. Additionally, SCG or VAL could reduce the accumulation of ADV in the renal interstitium by upregulating the expression of Oat1/3 and multidrug resistance-associated protein 4. Therefore, ADV accumulation in the renal interstitium could promote the degranulation of interstitial MCs and drive the development of renal fibrosis. SCG or VAL could ameliorate ADV-associated fibrosis by decreasing degranulation of MCs and accelerating renal clearance of ADV.
Topics: Adenine; Animals; Cell Degranulation; Disease Models, Animal; Fibrosis; Humans; Kidney Diseases; Kidney Tubules; Male; Mast Cells; Organophosphonates; Rats
PubMed: 35114312
DOI: 10.1016/j.toxlet.2022.01.018 -
BioRxiv : the Preprint Server For... Mar 2023Many poxviruses are significant human and animal pathogens, including viruses that cause smallpox and mpox. Identification of inhibitors of poxvirus replication is...
Many poxviruses are significant human and animal pathogens, including viruses that cause smallpox and mpox. Identification of inhibitors of poxvirus replication is critical for drug development to manage poxvirus threats. Here we tested two compounds, nucleoside trifluridine and nucleotide adefovir dipivoxil, for antiviral activities against vaccinia virus (VACV) and mpox virus (MPXV) in physiologically relevant primary human fibroblasts. Both trifluridine and adefovir dipivoxil potently inhibited replication of VACV and MPXV (MA001 2022 isolate) in a plaque assay. Upon further characterization, they both conferred high potency in inhibiting VACV replication with half maximal effective concentrations (EC ) at low nanomolar levels in our recently developed assay based on a recombinant VACV secreted Gaussia luciferase. Our results further validated that the recombinant VACV with Gaussia luciferase secretion is a highly reliable, rapid, non-disruptive, and simple reporter tool for identification and chracterization of poxvirus inhibitors. Both compounds inhibited VACV DNA replication and downstream viral gene expression. Given that both compounds are FDA-approved drugs, and trifluridine is used to treat ocular vaccinia in medical practice due to its antiviral activity, our results suggest that it holds great promise to further test trifluridine and adefovir dipivoxil for countering poxvirus infection, including mpox.
PubMed: 36993701
DOI: 10.1101/2023.03.23.533943 -
Drug Metabolism and Disposition: the... Sep 2023The proximal tubule plays an important role in the kidney and is a major site of drug interaction and toxicity. Analysis of kidney toxicity via in vitro assays is...
Improvement of Protein Expression Profile in Three-Dimensional Renal Proximal Tubular Epithelial Cell Spheroids Selected Based on OAT1 Gene Expression: A Potential In Vitro Tool for Evaluating Human Renal Proximal Tubular Toxicity and Drug Disposition.
The proximal tubule plays an important role in the kidney and is a major site of drug interaction and toxicity. Analysis of kidney toxicity via in vitro assays is challenging, because only a few assays that reflect functions of drug transporters in renal proximal tubular epithelial cells (RPTECs) are available. In this study, we aimed to develop a simple and reproducible method for culturing RPTECs by monitoring organic anion transporter 1 (OAT1) as a selection marker. Culturing RPTECs in spherical cellular aggregates increased OAT1 protein expression, which was low in the conventional two-dimensional (2D) culture, to a level similar to that in human renal cortices. By proteome analysis, it was revealed that the expression of representative two proximal tubule markers was maintained and 3D spheroid culture improved the protein expression of approximately 7% of the 139 transporter proteins detected, and the expression of 2.3% of the 4,800 proteins detected increased by approximately fivefold that in human renal cortices. Furthermore, the expression levels of approximately 4,800 proteins in three-dimensional (3D) RPTEC spheroids (for 12 days) were maintained for over 20 days. Cisplatin and adefovir exhibited transporter-dependent ATP decreases in 3D RPTEC spheroids. These results indicate that the 3D RPTEC spheroids developed by monitoring OAT1 gene expression are a simple and reproducible in vitro experimental system with improved gene and protein expressions compared with 2D RPTECs and were more similar to that in human kidney cortices. Therefore, it can potentially be used for evaluating human renal proximal tubular toxicity and drug disposition. SIGNIFICANCE STATEMENT: This study developed a simple and reproducible spheroidal culture method with acceptable throughput using commercially available RPTECs by monitoring OAT1 gene expression. RPTECs cultured using this new method showed improved mRNA/protein expression profiles to those in 2D RPTECs and were more similar to those of human kidney cortices. This study provides a potential in vitro proximal tubule system for pharmacokinetic and toxicological evaluations during drug development.
Topics: Humans; Kidney; Organic Anion Transport Protein 1; Kidney Tubules, Proximal; Membrane Transport Proteins; Gene Expression; Epithelial Cells
PubMed: 37385755
DOI: 10.1124/dmd.122.001171 -
Antiviral Research Feb 2021Since 2011, highly pathogenic pseudorabies virus (PRV) variants that emerged on many farms in China have posed major economic burdens to the animal industry and have...
Since 2011, highly pathogenic pseudorabies virus (PRV) variants that emerged on many farms in China have posed major economic burdens to the animal industry and have even recently caused several human cases of viral encephalitis. Currently, there are no approved effective drugs to treat PRV associated diseases in humans or pigs. Thus, it is important to develop a new effective drug for the treatment of PRV infection. To this end, we established a novel rapid method to screen drugs against PRV from 1818 kinds of small molecular drugs approved by the FDA. Using this method, we identified 21 kinds of them that can strongly suppress the proliferation of PRV. Mitoxantrone, puromycin dihydrochloride, mitoxantrone hydrochloride and adefovir dipivoxil effectively inhibited PRV in vitro. Of them, only adefovir dipivoxil could potently protect mice against lethal PRV infection. Our work identifies several kinds of potential therapeutics against PRV and may offer important guidance for controlling PRV epidemics and treating associated diseases in humans and animals.
Topics: Adenine; Animals; Antiviral Agents; Cell Line; Drug Discovery; Herpesvirus 1, Suid; High-Throughput Screening Assays; Mice; Mice, Inbred BALB C; Organophosphonates; Pseudorabies; Small Molecule Libraries; Swine; Virus Replication
PubMed: 33422610
DOI: 10.1016/j.antiviral.2021.105014 -
Journal of Pharmaceutical and... Apr 2022Maillard degradation products may lead to a decrease in active pharmaceutical ingredients and an increase in harmful substances. In this study, five acyclic nucleoside...
Maillard degradation products may lead to a decrease in active pharmaceutical ingredients and an increase in harmful substances. In this study, five acyclic nucleoside antiviral drugs (adefovir dipivoxil, famciclovir, tenofovir dipivoxil, acyclovir, and ganciclovir) were studied. Compatibility of APIs and lactose was performed, and the Maillard reaction products were monitored by HPLC-photodiode array detection and UHPLC-ESI-MS. Eight Maillard reaction products were detected, of which six were found to be new stable compounds (impurities 1-6) and were purified and identified by NMR spectroscopy. Moreover, the six new impurities were analyzed by MS/MS, and their mass spectrometric fragmentation mechanisms were proposed. The loss of a neutral fragment at 282 Da by the fragmentation of the lactose moiety was observed in the tandem mass spectra of all the impurities. This is the first systematic study of the Maillard reaction in the case of acyclic nucleosides antiviral drugs, and it has achieved good results. The results will be helpful for understanding the mass spectrometric fragmentation mechanisms of Maillard reaction products and the stability of acyclic nucleosides, and will provide suggestions for maintaining the stability and optimizing the storage and transportation conditions of these drugs.
Topics: Antiviral Agents; Chromatography, High Pressure Liquid; Maillard Reaction; Nucleosides; Tandem Mass Spectrometry
PubMed: 35134603
DOI: 10.1016/j.jpba.2022.114637 -
International Journal of Pharmaceutics Jul 2019In this paper, two novel polymorphs of adefovir dipivoxil-saccharin (AD-SAC) cocrystals, forms II and III, were prepared and characterized by PXRD, DSC, FT-IR and SEM....
In this paper, two novel polymorphs of adefovir dipivoxil-saccharin (AD-SAC) cocrystals, forms II and III, were prepared and characterized by PXRD, DSC, FT-IR and SEM. Polymorphic transformations of these two forms and the known form (form I) were also investigated. In comparison to form I, forms II and III of AD-SAC cocrystals showed different thermal behaviors on DSC, characteristic diffraction peaks on PXRD and absorption spectra on FT-IR. In addition, form I exhibited an irregular plate-like shape, while forms II and III showed as needle-like shape and stubby columnar shape, respectively. During the heating process on DSC, forms I and II underwent solid-solid transformations to form III with endothermic transition peaks, suggesting that forms I and II were enantiotropically related to form III. Furthermore, slurry conversion experiments in ethanol showed forms II and III would quickly convert to form I by solution-mediated transformation, indicating that form I was the most stable form among three forms of AD-SAC cocrystal from 15 to 50 °C.
Topics: Adenine; Crystallization; Organophosphonates; Saccharin; Thermodynamics
PubMed: 31152792
DOI: 10.1016/j.ijpharm.2019.05.071 -
Pharmaceutical Research Oct 2021This study aimed to improve the in vitro dissolution, permeability and oral bioavailability of adefovir dipivoxil (ADD) by cocrystal technology and clarify the important...
PURPOSE
This study aimed to improve the in vitro dissolution, permeability and oral bioavailability of adefovir dipivoxil (ADD) by cocrystal technology and clarify the important role of coformer selection on the cocrystal's properties.
METHODS
ADD was cocrystallized with three small molecules (i.e., paracetamol (PA), saccharin (SAC) and nicotinamide (NIC)), respectively. The obtained ADD-PA cocrystal was characterized by DSC, TGA, PXRD and FTIR. Comparative study on dissolution rates among the three ADD cocrystals were conducted in water and pH 6.8 phosphate buffer. Besides, effects of coformers on intestinal permeability of ADD were evaluated via in vitro Caco-2 cell model and in situ single-pass intestinal perfusion model in rats. Furthermore, in vivo pharmacokinetic study of ADD cocrystals was also compared.
RESULTS
Dissolution rates of ADD cocrystals were improved with the order of ADD-SAC cocrystal > ADD-PA cocrystal > ADD-NIC cocrystal. The permeability studies on Caco-2 cell model and single-pass intestinal perfusion model indicated that PA could enhance intestinal absorption of ADD by P-gp inhibition, while SAC and NIC did not. Further in vivo pharmacokinetic study showed that ADD-SAC cocrystal exhibited higher C (1.4-fold) and AUC (1.3-fold) of ADD than administration of ADD alone, and C and AUC of ADD-PA cocrystal were significantly enhanced by 2.1-fold and 2.2-fold, respectively, which was attributed to its higher dissolution and improved intestinal permeability.
CONCLUSION
Coformer selection had an important role on cocrystal's properties, and cocrystallization of ADD with a suitable coformer was an effective approach to enhance both dissolution and bioavailability of ADD.
Topics: Acetaminophen; Adenine; Animals; Area Under Curve; Caco-2 Cells; Cell Membrane Permeability; Chemistry, Pharmaceutical; Crystallization; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Models, Biological; Molecular Conformation; Niacinamide; Organophosphonates; Rats; Saccharin; Solubility; Water
PubMed: 34729701
DOI: 10.1007/s11095-021-03116-7