HPMPC (CIDOFOVIR), PMEA (ADEFOVIR) AND RELATED ACYCLIC NUCLEOSIDE PHOSPHONATE ANALOGS - A REVIEW OF THEIR PHARMACOLOGY AND CLINICAL POTENTIAL IN THE TREATMENT OF VIRAL-INFECTIONS

The acyclic nucleoside phosphonate (ANP) analogues are broad-spectrum antiviral agents, with potent and selective antiviral activity in vitr o and in vivo. The prototype compounds are: S)-1-(3-hydroxy-2-phosphon ylmethoxypropyl)cytosine (HPMPC, cidofovir), which is active against a wide variety of DNA viruses; 9-(2-phosphonylmethoxyethyl)adenine (PME A, adefovir), which is active against retro-, herpes- and hepadnavirus es, and (R)-9-(2-phosphonylmethoxypropyl) adenine (PMPA), which is act ive against retro- and hepadnaviruses. The antiviral action of the ANP analogues is based on a specific interaction of the active diphosphor ylated metabolite with the viral DNA polymerase. The long intracellula r half-life of the active metabolite accounts for the optimal efficacy in infrequent dosing schedules. The potential of HPMPC as a broad-spe ctrum anti-DNA virus agent, as originally observed in vitro and in viv o, has been confirmed in clinical trials. HPMPC has recently been comm ercially released in the USA For the treatment of cytomegalovirus reti nitis in AIDS patients. In addition, topical systemic HPMPC is being ( or will be) explored for use against other herpesviruses (i.e. herpes simplex virus, Epstein-Barr virus, or varicella-zoster virus), by aden oviruses, or by human papilloma- or polyomaviruses. Intravenous HPMPC is associated with dose-dependent nephrotoxicity, that should be count eracted by prehydration and concomitant administration of probenecid, and by the application of an infrequent dosing schedule. The oral prod rug of PMEA, bis(pivaloyloxymethyl)-PMEA, is currently being evaluated in patients infected with human immunodeficiency virus (HIV) or hepat itis B virus. Finally, preclinical data on the efficacy of PMPA in ani mal retrovirus models point to its potential usefulness against HIV in fections, when given either prophylactically or therapeutically in the treatment of established HIV infections.