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Clinical and Molecular Hepatology Sep 2018Fanconi syndrome is a dysfunction of the proximal renal tubules that results in impaired reabsorption and increased urinary loss of phosphate and other solutes. The...
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.
Topics: Adenine; Adult; Bone and Bones; Fanconi Syndrome; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Hepatitis B; Humans; Hypophosphatemia; Kidney Tubules, Proximal; Mitochondria; Organophosphonates; Osteomalacia
PubMed: 28859264
DOI: 10.3350/cmh.2017.0009 -
Zhonghua Gan Zang Bing Za Zhi =... Jan 2004
Review
Topics: Adenine; Antiviral Agents; Clinical Trials as Topic; Hepatitis B; Humans; Organophosphonates
PubMed: 14761297
DOI: No ID Found -
Revue de L'infirmiere Nov 2003
Topics: Adenine; Antiviral Agents; Drug Monitoring; Drug Prescriptions; Hepatitis B, Chronic; Humans; Organophosphonates; Patient Education as Topic; Patient Selection
PubMed: 14705256
DOI: No ID Found -
Chemotherapy 2018Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50-70% of patients achieving complete remission and less than 30% of adults having sustained...
Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50-70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this screen, we discovered adefovir dipi-voxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcome the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir were highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of > 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was through cell cycle arrest and DNA damage. Indeed, ODE-adefovir treatment induced cell cycle arrest in the S phase and increased levels of pH2Ax, indicating the induction of DNA damage. Furthermore, there was an increase in phospho-p53, transactivation of proapoptotic genes and activation of the intrinsic apoptotic pathway. Subsequent investigation unveiled strong synergism between ODE-adefovir and ara-C, making their coadministration of potential clinical benefit. Expression of MRP4, a nucleoside transporter, appeared to influence the response of AML cells to ODE-adefovir, as its inhibition potentiated ODE-adefovir killing. Taken together, our findings indicate that clinical development of ODE-adefovir or related compounds for the treatment of AML is warranted.
Topics: Adenine; Animals; Apoptosis; Caspases; Cell Cycle Checkpoints; Cytarabine; DNA Damage; Drug Compounding; Drug Resistance, Neoplasm; Drug Synergism; Female; Histones; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; Mice, SCID; Organophosphonates; Poly(ADP-ribose) Polymerases; Transplantation, Heterologous; Tumor Cells, Cultured
PubMed: 30372692
DOI: 10.1159/000491705 -
Life Sciences May 2019Common characteristics of drug induced nephrotoxicity are renal tubular and interstitial injury. Many studies have only focused on renal tubular injury. However, less is...
Common characteristics of drug induced nephrotoxicity are renal tubular and interstitial injury. Many studies have only focused on renal tubular injury. However, less is known about the effects of drugs in the renal interstitium on the nephrotoxicity. The aim of this study was to investigate the pharmacokinetics of adefovir (ADV) and the nephrotoxicity in the renal interstitium. Rats were treated with ADV alone or in combination with probenecid for 1, 7, 14, or 28 days. The renal interstitial fluid was collected by renal microdialysis. The concentration of ADV was determined by HPLC-MS/MS. Nephrotoxicity was evaluated by biochemical parameters or histological analysis. The results showed that organic anion transporters (OATs) inhibitor probenecid significantly increased the area under concentration-time curves (AUC) and peak concentration (C) of ADV in the renal interstitium, while the clearance (CL) in the renal interstitium was decreased in the ADV plus probenecid group compared to the ADV groups. After long-term treatment, interstitial fibrosis was present in the ADV plus probenecid group, whereas no trace of that could be detected in the ADV groups. Furthermore, a decrease was observed in the expression of OATs/Oats, which was dependent upon the concentrations and time of ADV treatment. In conclusion, it is possible that ADV could be accumulated in the interstitium when Oats were inhibited, which could cause renal interstitial fibrosis. Simply reducing cell uptake in long-term treatment might not be an effective method to protect against chronic nephrotoxicity.
Topics: Adenine; Animals; Antiviral Agents; Kidney Diseases; Kidney Tubules; Organic Anion Transporters; Organophosphonates; Rats; Rats, Wistar; Tissue Distribution
PubMed: 30902543
DOI: 10.1016/j.lfs.2019.03.042 -
Journal of Hepatology 2003
Review
Topics: Adenine; Antiviral Agents; Arabinofuranosyluracil; Deoxycytidine; Emtricitabine; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Nucleosides; Organophosphonates
PubMed: 14708699
DOI: 10.1016/s0168-8278(03)00334-9 -
Clinical Microbiology Reviews Oct 2003The acyclic nucleoside phosphonates HPMPC (cidofovir), PMEA (adefovir), and PMPA (tenofovir) have proved to be effective in vitro (cell culture systems) and in vivo... (Review)
Review
The acyclic nucleoside phosphonates HPMPC (cidofovir), PMEA (adefovir), and PMPA (tenofovir) have proved to be effective in vitro (cell culture systems) and in vivo (animal models and clinical studies) against a wide variety of DNA virus and retrovirus infections: cidofovir against herpesvirus (herpes simplex virus types 1 and 2 varicella-zoster virus, cytomegalovirus [CMV], Epstein-Barr virus, and human herpesviruses 6, 7, and 8), polyomavirus, papillomavirus, adenovirus, and poxvirus (variola virus, cowpox virus, vaccinia virus, molluscum contagiosum virus, and orf virus) infections; adefovir against herpesvirus, hepadnavirus (human hepatitis B virus), and retrovirus (human immunodeficiency virus types 1 [HIV-1] and 2 [HIV-2], simian immunodeficiency virus, and feline immunodeficiency virus) infections; and tenofovir against both hepadnavirus and retrovirus infections. Cidofovir (Vistide) has been officially approved for the treatment of CMV retinitis in AIDS patients, tenofovir disoproxil fumarate (Viread) has been approved for the treatment of HIV infections (i.e., AIDS), and adefovir dipivoxil (Hepsera) has been approved for the treatment of chronic hepatitis B. Nephrotoxicity is the dose-limiting side effect for cidofovir (Vistide) when used intravenously (5 mg/kg); no toxic side effects have been described for adefovir dipivoxil and tenofovir disoproxil fumarate, at the approved doses (Hepsera at 10 mg orally daily and Viread at 300 mg orally daily).
Topics: Adenine; Animals; Cidofovir; Cytosine; DNA Virus Infections; DNA Viruses; Humans; Organophosphonates; Organophosphorus Compounds; Retroviridae; Retroviridae Infections; Reverse Transcriptase Inhibitors; Tenofovir
PubMed: 14557287
DOI: 10.1128/CMR.16.4.569-596.2003 -
Clinical Therapeutics Dec 2013Hepatitis B virus infection remains 1 of the major health threats worldwide. Currently, lamivudine plus adefovir combination therapy or entecavir monotherapy is usually... (Comparative Study)
Comparative Study Meta-Analysis Review
Comparison of the efficacy of Lamivudine plus adefovir versus entecavir in the treatment of Lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis.
BACKGROUND
Hepatitis B virus infection remains 1 of the major health threats worldwide. Currently, lamivudine plus adefovir combination therapy or entecavir monotherapy is usually used for the treatment of patients with lamivudine-resistant chronic hepatitis B (CHB). However, there are few systematic comparisons between the efficacy of lamivudine plus adefovir and the efficacy of entecavir in the treatment of these patients.
OBJECTIVE
The goal of this systematic study and meta-analysis was to assess the efficacy of lamivudine plus adefovir compared with entecavir for the treatment of patients with lamivudine-resistant CHB.
METHODS
A comprehensive literature search of PUBMED, Web of Science, WANFANG database, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Review, were screened to obtain citations from January 1990 to January 2012 in this study. Data analysis was done by using the Review Manager Software 5.1.
RESULTS
Eight studies were suitable for analysis. A total of 696 patients with lamivudine-resistant CHB were studied and grouped according to treatment: 341 patients in the entecavir group and 355 patients in the lamivudine plus adefovir group. The results found that the rates of undetectable hepatitis B virus DNA levels, alanine aminotransferase normalization, hepatitis B e antigen loss, and hepatitis B e antigen seroconversion were not significantly different between the lamivudine plus adefovir group and the entecavir group. Moreover, the rate of adverse reactions was also not significantly different between the 2 groups. However, virologic breakthrough for the patients with lamivudine resistance was higher in the entecavir group than in the lamivudine plus adefovir group.
CONCLUSIONS
For these CHB patients with lamivudine resistance, lamivudine plus adefovir was a better treatment option than entecavir alone.
Topics: Adenine; Antiviral Agents; Clinical Trials as Topic; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Organophosphonates; Treatment Outcome
PubMed: 24238791
DOI: 10.1016/j.clinthera.2013.10.002 -
Scandinavian Journal of Infectious... Dec 2011
Topics: Adenine; Aged; Humans; Hypophosphatemia; Male; Organophosphonates; Osteomalacia; Radionuclide Imaging; Whole Body Imaging
PubMed: 21609200
DOI: 10.3109/00365548.2011.581307 -
European Journal of Clinical... Jul 2024Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal...
PURPOSE
Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CL) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail.
METHODS
Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination.
RESULTS
A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h vs. 5.18 h) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (K) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (V) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min.
CONCLUSION
The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high K value suggests that assessing renal OAT1 activity by CL has no relevant misspecification error with the cocktail doses used.
Topics: Humans; Organophosphonates; Adenine; Male; Adult; Models, Biological; Female; Organic Anion Transport Protein 1; Drug Interactions; Phenotype; Middle Aged; Young Adult; Digoxin; Metformin; Sitagliptin Phosphate; Biological Availability
PubMed: 38546841
DOI: 10.1007/s00228-024-03673-x