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Biological & Pharmaceutical Bulletin 2023Uricosuric agents lower serum uric acid levels by increasing urinary excretion via inhibition of urate transporter 1 (URAT1), urate reabsorption transporter in the renal...
Uricosuric agents lower serum uric acid levels by increasing urinary excretion via inhibition of urate transporter 1 (URAT1), urate reabsorption transporter in the renal proximal tubules. Probenecid and benzbromarone have been used as uricosurics, but these drugs inhibit organic anion transporters (OATs) in addition to URAT1. In this study, we investigated whether uricosuric agents interacted with adefovir, known as a substrate for OAT1, using Sprague-Dawley (SD) rats. Furthermore, involvement of other transporters, multi-drug resistance protein 2 (MRP2) in this interaction was examined using Mrp2-deficient rats. Probenecid and lesinurad increased plasma adefovir concentrations and decreased kidney-to-plasma partition coefficient (Kp) in these rats, presumably by inhibiting Oat1. Although benzbromarone had no effect on plasma adefovir concentration, it increased the Kp to 141% in SD rats. Since this effect was abolished in Mrp2-deficient rats, together with the MRP2 inhibition study, it is suggested that benzbromarone inhibits Mrp2-mediated adefovir excretion from the kidney. In contrast, dotinurad, a novel uricosuric agent that selectively inhibits URAT1, had no effect on the plasma and kidney concentrations of adefovir. Therefore, due to the lack of interaction with adefovir, dotinurad is expected to have low drug-drug interaction risk mediated by OAT1, and also by MRP2.
Topics: Rats; Animals; Uricosuric Agents; Benzbromarone; Probenecid; Uric Acid; Rats, Sprague-Dawley; Kidney; Organic Anion Transporters
PubMed: 36724945
DOI: 10.1248/bpb.b22-00384 -
Frontiers in Oncology 2022In this study, we aimed to perform a network meta-analysis to compare the effectiveness of NAs in decreasing the reactivation of HBV, reducing chemotherapy disruption,...
OBJECTIVE
In this study, we aimed to perform a network meta-analysis to compare the effectiveness of NAs in decreasing the reactivation of HBV, reducing chemotherapy disruption, and improving survival in oncology patients.
METHODS
Relevant randomized controlled trials (RCT) evaluating the impact of NAs in HBV infected-related oncology patients were retrieved from electronic databases. The outcome indicators included reactivation rate, survival rate of 1 to 3 years after treatment, and chemotherapy disruption rate. The studies were evaluated for bias using the RCT risk of bias assessment tool recommended in the Cochrane Handbook. The risk ratio (RR) was used to compare the outcome indicators for the anti-viral treatment, and the surface under the cumulative ranking curves (SUCRA) was used to identify the optimal therapeutic regime.
RESULTS
A total of 67 trials containing 5722 patients were included in this study. Regarding the reduction of reactivation rate, entecavir, lamivudine, adefovir alone were less effective than the combination of lamivudine and entecavir (94.9%), with RR values ranging from 3.16 to 3.73. However, based on SUCRA, the efficacy of telbivudine (80.3%) and the combination of lamivudine and adefovir dipivoxil (58.8%) were also acceptable. Entecavir (RR values ranging from 1.25 to 1.50) and lamivudine (RR values ranging from 1.27 to 1.35) can prolong the survival rate of patients at 1-3 years, and were better than adefovir dipivoxil in the comparison of 1-year survival rate. The RR values were 1.18 and 1.19, respectively. And entecavir 's ranking in SUCRA was more stable. Entecavir, lamivudine, and tenofovir all reduced chemotherapy interruption rates compared with no antiviral therapy, especially for tenofovir.
CONCLUSIONS
Current evidence shows that lamivudine combined with entecavir, telbivudine, and lamivudine combined with adefovir dipivoxil were the most effective in preventing virus reactivation in HBV infected-related cancer patients treated with chemotherapy. Entecavir had the most stable effect on survival, while tenofovir had the best impact on reducing the chemotherapy disruption rate. Due to limited quality and quantity of the included studies, more high-quality studies are required to verify the above conclusions.
SYSTEMATIC REVIEW REGISTRATION
PROSPEROI [https://www.crd.york.ac.uk/PROSPERO/index.php], identifier CRD4202250685.
PubMed: 36727050
DOI: 10.3389/fonc.2022.1050714 -
European Journal of Pharmaceutical... Jul 2023Cocktails of transporter probe drugs are used in vivo to assess transporter activity and respective drug-drug interactions. An inhibitory effect of components on...
PURPOSE
Cocktails of transporter probe drugs are used in vivo to assess transporter activity and respective drug-drug interactions. An inhibitory effect of components on transporter activities should be ruled out. Here, for a clinically tested cocktail consisting of adefovir, digoxin, metformin, sitagliptin, and pitavastatin, inhibition of major transporters by individual probe substrates was investigated in vitro.
METHODS
Transporter transfected HEK293 cells were used in all evaluations. Cell-based assays were applied for uptake by human organic cation transporters 1/2 (hOCT1/2), organic anion transporters 1/3 (hOAT1/3), multidrug and toxin extrusion proteins 1/2K (hMATE1/2K), and organic anion transporter polypeptide 1B1/3 (hOATP1B1/3). For P-glycoprotein (hMDR1) a cell-based efflux assay was used whereas an inside-out vesicle-based assay was used for the bile salt export pump (hBSEP). All assays used standard substrates and established inhibitors (as positive controls). Inhibition experiments using clinically achievable concentrations of potential perpetrators at the relevant transporter expression site were carried out initially. If there was a significant effect, the inhibition potency (K) was studied in detail.
RESULTS
In the inhibition tests, only sitagliptin had an effect and reduced hOCT1- and hOCT2- mediated metformin uptake and hMATE2K mediated MPP uptake by more than 70%, 80%, and 30%, respectively. The ratios of unbound C (observed clinically) to K of sitagliptin were low with 0.009, 0.03, and 0.001 for hOCT1, hOCT2, and hMATE2K, respectively.
CONCLUSION
The inhibition of hOCT2 in vitro by sitagliptin is in agreement with the borderline inhibition of renal metformin elimination observed clinically, supporting a dose reduction of sitagliptin in the cocktail.
Topics: Humans; Organic Cation Transport Proteins; HEK293 Cells; Biological Transport; Sitagliptin Phosphate; Metformin; Organic Cation Transporter 2; Drug Interactions
PubMed: 37142000
DOI: 10.1016/j.ejps.2023.106459 -
Experimental Hematology & Oncology Nov 2022Acute promyelocytic leukemia (APL) is highly aggressive and is frequently associated with disseminated intravascular coagulation and high early death rates. Although...
Acute promyelocytic leukemia (APL) is highly aggressive and is frequently associated with disseminated intravascular coagulation and high early death rates. Although all-trans retinoic acid (RA) induces complete remission in a high proportion of patients with APL, there are limited treatments for APL patients with RA resistance. Here we report an atypical APL patient, with an APL-like disease that developed very slowly without anti-leukemia therapy for nearly 2 years. During that time, the patient only intermittently received anti-HBV drugs, i.e., the combination of adefovir dipivoxil (ADV) and entecavir (ETV), leading us to hypothesize that ADV and/or ETV could inhibit APL progression. Our results showed that anti-HBV drugs ADV and ETV both exhibited significantly inhibitory effects on APL cells, and ADV indicated a much greater cytotoxic effect than ETV on APL cells. We further found that ADV significantly promoted APL cell differentiation and apoptosis, thereby restraining the progression of APL. Most importantly, our study uncovered a novel mechanism of ADV prohibiting APL progression, which was mediated, at least in part, by inhibition of TRIB3 and degradation of the oncoprotein PML-RARA, therefore leading to APL cell differentiation and apoptosis. Taken together, our study demonstrated that ADV, an anti-HBV drug, had significantly inhibitory effects on APL, and provided a novel therapeutic strategy for APL patients with RA resistance.
PubMed: 36404334
DOI: 10.1186/s40164-022-00355-1 -
Nucleos(t)ide analogues and Hepatitis B virus-related hepatocellular carcinoma: A literature review.Antiviral Chemistry & Chemotherapy 2020Hepatitis B virus is mainly considered to cause hepatocellular carcinoma which is the fourth leading cause of cancer-related mortality worldwide. Treatment of Hepatitis... (Review)
Review
Hepatitis B virus is mainly considered to cause hepatocellular carcinoma which is the fourth leading cause of cancer-related mortality worldwide. Treatment of Hepatitis B virus with nucleos(t)ide analogues can decrease the progression of the disease and subsequently decreases the incidence of hepatocellular carcinoma. In this review, we have discussed the different classes of nucleos(t)ide analogues used in the treatment of Hepatitis B virus and their relationship with the development of hepatocellular carcinoma. Furthermore, we discussed the effect of treatment of Hepatitis B virus with Nucleoside analogues (NAs) before, during and after surgery, chemoembolization, radiofrequency ablation, and chemotherapy for the treatment of hepatocellular carcinoma.
Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B virus; Humans; Liver Neoplasms; Microbial Sensitivity Tests; Nucleosides; Nucleotides
PubMed: 32418480
DOI: 10.1177/2040206620921331 -
JHEP Reports : Innovation in Hepatology Apr 2023Patterns of liver HBV antigen expression have been described but not quantified at single-cell resolution. We applied quantitative techniques to liver biopsies from...
BACKGROUND & AIMS
Patterns of liver HBV antigen expression have been described but not quantified at single-cell resolution. We applied quantitative techniques to liver biopsies from individuals with chronic hepatitis B and evaluated sampling heterogeneity, effects of disease stage, and nucleos(t)ide (NUC) treatment, and correlations between liver and peripheral viral biomarkers.
METHODS
Hepatocytes positive for HBV core and HBsAg were quantified using a novel four-plex immunofluorescence assay and image analysis. Biopsies were analysed from HBeAg-positive (n = 39) and HBeAg-negative (n = 75) participants before and after NUC treatment. To evaluate sampling effects, duplicate biopsies collected at the same time point were compared. Serum or plasma samples were evaluated for levels of HBV DNA, HBsAg, hepatitis B core-related antigen (HBcrAg), and HBV RNA.
RESULTS
Diffusely distributed individual HBV core+ cells and foci of HBsAg+ cells were the most common staining patterns. Hepatocytes positive for both HBV core and HBsAg were rare. Paired biopsies revealed large local variation in HBV staining within participants, which was confirmed in a large liver resection. NUC treatment was associated with a >100-fold lower median frequency of HBV core+ cells in HBeAg-positive and HBeAg-negative participants, whereas reductions in HBsAg+ cells were not statistically significant. The frequency of HBV core+ hepatocytes was lower in HBeAg-negative participants than in HBeAg-positive participants at all time points evaluated. Total HBV+ hepatocyte burden correlated with HBcrAg, HBV DNA, and HBV RNA only in baseline HBeAg-positive samples.
CONCLUSIONS
Reductions in HBV core+ hepatocytes were associated with HBeAg-negative status and NUC treatment. Variation in HBV positivity within individual livers was extensive. Correlations between the liver and the periphery were found only between biomarkers likely indicative of cccDNA (HBV core+ and HBcrAg, HBV DNA, and RNA).
IMPACT AND IMPLICATIONS
HBV infects liver hepatocyte cells, and its genome can exist in two forms that express different sets of viral proteins: a circular genome called cccDNA that can express all viral proteins, including the HBV core and HBsAg proteins, or a linear fragment that inserts into the host genome typically to express HBsAg, but not HBV core. We used new techniques to determine the percentage of hepatocytes expressing the HBV core and HBsAg proteins in a large set of liver biopsies. We find that abundance and patterns of expression differ across patient groups and even within a single liver and that NUC treatment greatly reduces the number of core-expressing hepatocytes.
PubMed: 36908748
DOI: 10.1016/j.jhepr.2022.100664 -
Hepatology (Baltimore, Md.) Jul 2022HBV can integrate in the host genome of the hepatocyte and recent findings suggest that integrated HBV contributes to the persistent production of viral proteins. Here,...
BACKGROUND AND AIMS
HBV can integrate in the host genome of the hepatocyte and recent findings suggest that integrated HBV contributes to the persistent production of viral proteins. Here, we quantified the levels of integrated HBV in patients with chronic hepatitis B (CHB) and analyzed the relation between HBV integration, virological activity (plasma HBV DNA and HBsAg levels), and clinical outcomes.
APPROACH AND RESULTS
We developed and validated a multistep Arthrobacter luteus (Alu)-PCR that specifically amplifies integrated HBV and RT-Alu-PCR detecting mRNA transcripts derived from integrated HBV. Pretreatment liver biopsy samples and baseline characteristics of 124 patients with CHB either treated for 48 weeks with pegylated interferon plus adefovir or tenofovir or receiving no treatment were available for analysis. Integrated HBV sequences containing open reading frame S and X (but not C) and S and X mRNA transcripts derived from integrated HBV could be detected and quantified in liver biopsies. Integrated HBV levels correlated with HBV DNA, HBsAg, alanine aminotransferase plasma levels, and the liver histology activity index but not to levels of intrahepatic covalently closed circular DNA (cccDNA), plasma pregenomic RNA, or hepatitis B core-related antigen. Multivariable logistic regression analysis showed that lower baseline HBV integration levels were independently associated with HBsAg loss (functional cure) within 5 years follow-up.
CONCLUSIONS
Integrated HBV levels are strongly correlated with surrogate markers for virological activity but not to cccDNA levels and are predictive for HBsAg loss. Our data suggest that integrated HBV is closely related to HBV replication and may therefore be an important tool in the evaluation and development of treatment modalities aiming to cure CHB.
Topics: Antiviral Agents; DNA, Circular; DNA, Viral; Hepatitis B Core Antigens; Hepatitis B Surface Antigens; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver; RNA, Messenger
PubMed: 35073596
DOI: 10.1002/hep.32352 -
Mathematical Biosciences and... Oct 2019To compare the 2-year efficacy and safety of combination therapy with entecavir (ETV) and adefovir dipivoxil (ADV) to that of tenofovir disoproxil fumarate (TDF)... (Comparative Study)
Comparative Study Randomized Controlled Trial
Compare with safety and efficacy of entecavir and adefovir dipivoxil combination therapy and tenofovir disoproxil fumarate monotherapy for chronic hepatitis B patient with adefovir-resistant.
To compare the 2-year efficacy and safety of combination therapy with entecavir (ETV) and adefovir dipivoxil (ADV) to that of tenofovir disoproxil fumarate (TDF) monotherapy in treatment of patients with adefovir drug-resistant chronic hepatitis B. HBeAg-positive CHB patients (n = 100) with adefovir-resistance (rtA181T/V and/or rtN236T) were enrolled. Patients were treated with either ETV 0.5 mg plus ADV 10 mg per day (n = 52) or TDF 300 mg per day (n = 48) for 48 weeks. Tests for liver and kidney function, Serum Phosphorus, HBV serum markers, HBV DNA load and ultrasonography of liver were performed every 3 months. Student's t-test and χ test were used to compare the efficacy, side effects in the two groups. Fifty-two patients in ETV + ADV group and forty-eight patients in TDF group were followed-up for 96 weeks. HBV DNA undetectable rate were 76.9% versus 81.3% (P = 0.631) at week 48, and 92.3% versus 95.8% (P = 0.679) at week 96 in ETV + ADV combination therapy and TDF monotherapy group respectively. Serum ALT normalized rate were 84.6% versus 87.5% (P = 0.777) at week 48, and 92.3% versus 95.8% (P = 0.679) at week 96 in ETV+ADV combination therapy and TDF monotherapy group respectively. But the level of serum Phosphorus was significantly lower in ETV + ADV combination therapy group compare with TDF monotherapy group (1.13 ±0.15 versus 1.22 ±0.16, P = 0.004) at week 96. Both ETV + ADV combination therapy and TDF monotherapy provided effective treatments in chronic hepatitis B with adefovir-resistant. However, it was associated with poor serological responses up to week 96. The long term treatment of hepatitis B with ETV (0.5 mg/day) combination of ADV (10 mg/day) can potentially cause hypophosphatemia and renal impairment, so regular monitoring of serum phosphate, serum creatinine and evaluation of eGFR is needed.
Topics: Adenine; Adult; Antiviral Agents; Case-Control Studies; Creatinine; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B; Hepatitis B virus; Humans; Male; Middle Aged; Mutation; Organophosphonates; Phosphates; Phosphorous Acids; Prospective Studies; Treatment Outcome; Viral Load; Young Adult
PubMed: 31731368
DOI: 10.3934/mbe.2020032 -
International Journal of Rheumatic... Jan 2024
Topics: Humans; Spondylitis, Ankylosing; Osteochondrosis; Hypophosphatemia; Organophosphonates; Adenine
PubMed: 38287538
DOI: 10.1111/1756-185X.15040 -
International Journal of Cancer Sep 2020Replication stress is a common feature of cancer cells. Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) signalling, a DNA damage repair (DDR) pathway, is...
Replication stress is a common feature of cancer cells. Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) signalling, a DNA damage repair (DDR) pathway, is activated by regions of single-stranded DNA (ssDNA) that can arise during replication stress. ATR delays cell cycle progression and prevents DNA replication fork collapse, which prohibits cell death and promotes proliferation. Several ATR inhibitors have been developed in order to restrain this protective mechanism in tumours. It is known, however, that despite other effective anticancer chemotherapy treatments targeting DDR pathways, resistance occurs. This begets the need to identify combination treatments to overcome resistance and prevent tumour cell growth. We conducted a drug screen to identify potential synergistic combination treatments by screening an ATR inhibitor (VE822) together with compounds from a bioactive small molecule library. The screen identified adefovir dipivoxil, a reverse transcriptase inhibitor and nucleoside analogue, as a compound that has increased cytotoxicity in the presence of ATR, but not ATM or DNA-dependant protein kinase (DNA-PK) inhibition. Here we demonstrate that adefovir dipivoxil induces DNA replication stress, activates ATR signalling and stalls cells in S phase. This simultaneous induction of replication stress and inhibition of ATR signalling lead to a marked increase in pan-nuclear γH2AX-positive cells, ssDNA accumulation and cell death, indicative of replication catastrophe.
Topics: Adenine; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Cell Death; Cell Line, Tumor; Cell Proliferation; DNA Replication; Humans; Organophosphonates; Protein Kinase Inhibitors; Signal Transduction
PubMed: 32159854
DOI: 10.1002/ijc.32966