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Antiviral Therapy Apr 2022Adefovir, a nucleotide analog developed by John Martin, was a major breakthrough in the treatment of chronic Hepatitis B. Prior to adefovir, Hepatitis B treatment was... (Review)
Review
Adefovir, a nucleotide analog developed by John Martin, was a major breakthrough in the treatment of chronic Hepatitis B. Prior to adefovir, Hepatitis B treatment was limited to two therapeutic modalities, either interferon, which carried significant side effects and was efficacious in a minority of patients, or lamivudine which showed no durable effects with short-term use and a high rate of resistance with long-term use. Adefovir was found to be effective in suppressing viral replication and in resolving the hepatic inflammation associated with hepatitis B with only rare instances of resistance. In this article, we appreciate John Martin's contribution to science and medicine as we review the landmark trials of adefovir that brought forth a new era of treatment of Hepatitis B.
Topics: Adenine; Drug Resistance, Viral; Hepatitis B; Humans; Lamivudine; Organophosphonates
PubMed: 35499182
DOI: 10.1177/13596535211067605 -
Medicina Clinica Mar 2022
Topics: Adenine; Humans; Hypophosphatemia; Organophosphonates; Osteomalacia
PubMed: 34256937
DOI: 10.1016/j.medcli.2021.05.019 -
Expert Review of Anti-infective Therapy Aug 2004Adefovir dipivoxil (Hepsera, Gilead Sciences) is a prodrug of adefovir, with potent antiviral activity against hepatitis B virus. Adefovir dipivoxil therapy, 10 mg daily... (Review)
Review
Adefovir dipivoxil (Hepsera, Gilead Sciences) is a prodrug of adefovir, with potent antiviral activity against hepatitis B virus. Adefovir dipivoxil therapy, 10 mg daily for 48 weeks, is effective in hepatitis B e antigen-positive and -negative chronic hepatitis B. In hepatitis B e antigen-negative chronic hepatitis B, adefovir dipivoxil was recently found to maintain its efficacy even after 3 years of therapy. Adefovir dipivoxil is effective in patients with compensated or decompensated chronic viral B liver disease, and in pre- and post-transplant hepatitis B virus patients who develop resistance to lamivudine (Epivir, GlaxoSmithKline). It is well-tolerated and safe even after the third year of long-term therapy, and is associated with low rates of viral resistance. All these characteristics make adefovir dipivoxil an important drug for the treatment of hepatitis B virus infection and an excellent candidate for long-term maintenance therapy in chronic viral B liver disease.
Topics: Adenine; Antiviral Agents; Clinical Trials as Topic; Drug Approval; Drug Resistance, Viral; HIV Infections; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates
PubMed: 15482214
DOI: 10.1586/14787210.2.4.475 -
Journal of Pharmacy & Pharmaceutical... 2018Adefovir is an antiviral drug that exhibits high hydrophilic properties and negligible bioavailability (less than 12%). It is only applied in the form of the ester... (Review)
Review
PURPOSE
Adefovir is an antiviral drug that exhibits high hydrophilic properties and negligible bioavailability (less than 12%). It is only applied in the form of the ester prodrug adefovir dipivoxil (ADV). The oral bioavailability of ADV is limited (32% to 45%) by its low permeability (Class 3) and biological conversion of the prodrug to adefovir. Ion-pair formation is considered as an alternative approach to a covalent prodrug (ADV) to enhance intestinal permeation of adefovir.
METHODS
The effect of various counter-ions (anionic, cationic and two quaternary ammonium salts) on the lipophilicity of adefovir was investigated by means of the n-octanol/buffer partitioning system, an in vitro transport model (PAMPA) and a biological membrane (everted gut sac).
RESULTS
Quaternary ammonium salts, cetylpyridinium chloride (CPC) and cetrimide enhanced the lipophilicity of adefovir 136- and 87-fold, respectively. The apparent permeability of adefovir in combination with CPC (counter-ion) was 2.5-fold greater than ADV permeability in the PAMPA model. The apparent permeability of adefovir-CPC (counter-ion) was 1.3-fold greater than that of adefovir dipivoxil permeability in a biologic membrane (everted gut sac).
CONCLUSION
These results suggest that the adefovir-CPC ion-paired system has potential for improving the permeation of adefovir across the intestinal membrane. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Topics: Adenine; Animals; Antiviral Agents; Cell Membrane; Cetrimonium; Cetylpyridinium; Humans; Intestinal Mucosa; Ions; Organophosphonates; Prodrugs; Quaternary Ammonium Compounds
PubMed: 29789103
DOI: 10.18433/jpps29394 -
International Journal of Rheumatic... Jan 2024
Topics: Humans; Spondylitis, Ankylosing; Osteochondrosis; Hypophosphatemia; Organophosphonates; Adenine
PubMed: 38287538
DOI: 10.1111/1756-185X.15040 -
Journal of Hepatology Aug 2005
Review
Topics: Adenine; Antiviral Agents; Drug Therapy, Combination; Hepatitis B; Hepatitis B e Antigens; Hepatitis B virus; Humans; Lamivudine; Organophosphonates; Reverse Transcriptase Inhibitors; Treatment Outcome; Virulence
PubMed: 15975684
DOI: 10.1016/j.jhep.2005.05.011 -
American Family Physician Dec 2003
Review
Topics: Adenine; Antiviral Agents; Hepatitis B, Chronic; Humans; Organophosphonates
PubMed: 14705763
DOI: No ID Found -
Canadian Journal of Gastroenterology =... Nov 2006
Review
Topics: Adenine; Antiviral Agents; Canada; Drug Utilization; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Organophosphonates
PubMed: 17111050
DOI: 10.1155/2006/826093 -
Virology Journal Mar 2011Chronic viral hepatitis B remains a global public health concern. Currently, several drugs, such as tenofovir and adefovir, are recommended for treatment of patients... (Comparative Study)
Comparative Study Meta-Analysis Review
Chronic viral hepatitis B remains a global public health concern. Currently, several drugs, such as tenofovir and adefovir, are recommended for treatment of patients with chronic hepatitis B. tenofovir is a nucleoside analog with selective activity against hepatitis b virus and has been shown to be more potent in vitro than adefovir. But the results of trials comparing tenofovir and adefovir in the treatment of chronic hepatitis B were inconsistent. However, there was no systematic review on the comparison of the efficacy of tenofovir and adefovir in the treatment of chronic hepatitis B. To evaluate the comparison of the efficacy of tenofovir and adefovir in the treatment of chronic hepatitis B we conducted a systematic review and meta-analysis of clinical trials. We searched PUBMED, Web of Science, EMBASE, CNKI, VIP database, WANFANG database, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Review. Finally six studies were left for analysis which involved 910 patients in total, of whom 576 were included in tenofovir groups and 334 were included in adefovir groups. At the end of 48-week treatment, tenofovir was superior to adefovir at the HBV-DNA suppression in patients[RR = 2.59; 95%CI(1.01-6.67), P = 0.05]. While there was no significant difference in the ALT normalization[RR = 1.15; 95%CI(0.96-1.37), P = 0.14], HBeAg seroconversion[RR = 1.32; 95%CI(1.00-1.75), P = 0.05] and HBsAg loss rate[RR = 1.19; 95%CI(0.74-1.91), P = 0.48]. More high-quality, well-designed, randomized controlled, multi-center trails are clearly needed to guide evolving standards of care for chronic hepatitis B.
Topics: Adenine; Antiviral Agents; Controlled Clinical Trials as Topic; Hepatitis B virus; Hepatitis B, Chronic; Humans; Organophosphonates; Tenofovir; Treatment Outcome
PubMed: 21388525
DOI: 10.1186/1743-422X-8-111 -
Clinical Pharmacokinetics Feb 1999Cidofovir and adefovir are members of a new class of antiviral compounds. They are acyclic phosphonate analogues of deoxynucleoside monophosphates. Both compounds... (Review)
Review
Cidofovir and adefovir are members of a new class of antiviral compounds. They are acyclic phosphonate analogues of deoxynucleoside monophosphates. Both compounds undergo intracellular activation to form diphosphates that are potent inhibitors of viral DNA polymerases. Cidofovir has broad spectrum antiviral activity against herpesviruses, papillomaviruses and poxviruses, whereas adefovir has potent activity against retroviruses and certain DNA viruses, including herpesviruses and hepadnaviruses. Intravenous cidofovir is approved for treatment of cytomegalovirus retinitis in patients with AIDS. Cidofovir and adefovir are dianionic at physiological pH and have low oral bioavailability in animals and humans. After intravenous administration to HIV-infected patients, the pharmacokinetics of both drugs are independent of dose and are consistent with preclinical data. Systemic exposure is proportional to the intravenous dose and both drugs are cleared by the kidney and excreted extensively as unchanged drug in the urine. Intracellular activation of a small fraction (< 10%) of the dose by cellular kinases leads to prolonged antiviral effects that are not easily predicted from conventional pharmacokinetic studies. The observed rate of elimination of cidofovir and adefovir from serum may not reflect the true duration of action of these drugs, since the antiviral effect is dependent on concentrations of the active phosphorylated metabolites that are present within cells. For both drugs, > 90% of an intravenous dose is recovered unchanged in the urine over 24 hours. Metabolism does not contribute significantly to the total clearance of either drug. Concomitant oral probenecid decreases both the renal clearance of cidofovir and the incidence of nephrotoxicity, presumably by blocking its active tubular secretion. This is the basis of the clinical use of concomitant probenecid as a nephroprotectant during cidofovir therapy. Subcutaneous administration produces exposure equivalent to that following intravenous administration. Drug interaction studies with cidofovir are ongoing, but there is no evidence of an interaction between zidovudine and either cidofovir or adefovir. Clearance of cidofovir in patients with renal impairment showed a linear relationship to creatinine clearance. The low oral bioavailability of adefovir has led to the development of an oral prodrug, adefovir dipivoxil, currently in development for the treatment of HIV and hepatitis B infections.
Topics: Adenine; Administration, Oral; Animals; Antiviral Agents; Cidofovir; Cytosine; Drug Interactions; Humans; Infusions, Intravenous; Organophosphonates; Organophosphorus Compounds; Probenecid; Renal Insufficiency
PubMed: 10092959
DOI: 10.2165/00003088-199936020-00004