Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections

Abstract

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)

In vitro antitumor and antiviral activities of new benzothiazole and 1,3,4-oxadiazole-2-thione derivatives

“…Thus, no selective anti-HIV activity could be witnessed (EC 50 > 100 mg mL -1 ). As compared to the known antiviral agent Cidofovir (19), no activity was found for any of the compounds at non-toxic concentrations.…”

BK Nephropathy in Renal Transplant Patients: Review

“…Sidofovirin nefrotoksik etkisi yüksektir, proteinüri ve %20 oranında renal yetmezliği kötüleştirebilmektedir. [53][54][55] Diyabet ve fokal segmental glomerüloskleroza bağlı kronik böbrek yetmezliği gelişen ve nakil olan iki hastada (sırasıyla 30. ve ikinci aylarda) BKVN gelişmiştir. Sidofovir (0,25 mg/kg) tedavisi ile virüs klerensi sağlanmış ve greft fonksiyonları korunmuştur.…”

Tenofovir and its potential in the treatment of hepatitis B virus

“…55 Toxicity, as shown by peripheral neuropathy, lipodystrophy, lactic acidosis and pancreatitis, appears associated with mitochondrial dysfunction. 10,55 Because TDF may cause nephrotoxic effects, periodic monitoring of renal function during nucleotide therapy is advisable, 1,6,55 but we can conclude that this drug, alone, is characterized by a relative lack of nephrotoxicity and appears an optimal drug for post-transplantation HBV prophylaxis. 57 TDF also showed in vitro an hematopoietic toxicity, compared with other antiviral molecules, superior only to LAM.…”

“…As ADV, its congener, it possess a phosphonate group attached to an acyclic nucleotide moiety through a stable P-C bond. 10 With this confi guration it bypasses the fi rst phosphorylation kinase step that is needed to activate various nucleoside analogs 2 : it needs just two, instead of three, phosphorylation steps to reach the active metabolite stage. Therefore, it does not depend on the virus-induced kinase to exert its antiviral action and may be expected to have selective activity against a broad range of DNA virus, including hepadnaviruses (as HBV) and retroviruses (as human immunodefi ciency virus, HIV).…”

“…Therefore, it does not depend on the virus-induced kinase to exert its antiviral action and may be expected to have selective activity against a broad range of DNA virus, including hepadnaviruses (as HBV) and retroviruses (as human immunodefi ciency virus, HIV). 10 TDF, diphosphorylated, competes with natural triphosphate deoxynucleosides for binding to the active site of HBV polymerase, and its incorporation at the end of the growing DNA terminates chain elongation. Furthermore TDF has a higher affi nity for the viral DNA polymerases than for human cellular DNA polymerases α, β, γ, δ and ε.…”