Foscarnet

Abstract

The pyrophosphate analogue, foscarnet, selectively inhibits the DNA polymerase of human herpes viruses, including cytomegalovirus, and the reverse transcriptase of HIV. Viral replication is therefore prevented, but resumes when the drug is cleared from infected cells. In vitro, the combination of foscarnet and zidovudine (azidothymidine) has an additive effect against cytomegalovirus and acts synergistically against HIV. An improvement in cytomegalovirus retinitis is obtained in over 85% of affected AIDS patients during foscarnet induction therapy, but relapse usually occurs within a month of ceasing treatment. There is a similar duration of remission during maintenance therapy given for 5 days each week, but this can be extended 4- to 5-fold with daily administration of higher doses. In allograft recipients, progression of retinitis can be halted by foscarnet until immune function recovers and eradicates the virus. The incidence of acute renal failure, which is common during foscarnet therapy, may be reduced by dosage adjustment and adequate prehydration. Anaemia, phlebitis, nausea and vomiting, and disturbances in serum calcium and phosphate levels, perhaps resulting from uptake of foscarnet into bone or chelation with ionised calcium, have also been associated with administration of the drug. Cytomegalovirus retinitis is difficult to treat, with few therapeutic options available. Although treatment with foscarnet produces some severe adverse effects, with care these can be minimised, and the drug produces clinical improvement in a large proportion of patients; this is a highly encouraging finding at this stage in its development. Preliminary comparative data indicate that foscarnet and ganciclovir are similarly effective, but foscarnet may have some theoretical advantages in AIDS patients since it can be used in combination with zidovudine without potentiating myelosuppression.

Preclinical and Toxicology Studies of 1263W94, a Potent and Selective Inhibitor of Human Cytomegalovirus Replication

“…Problems associated with each of these therapies include toxicities, such as bone marrow suppression (granulocytopenia, anemia, and thrombocytopenia), with GCV (8,18) and nephrotoxicity with CDV (14,15) and PFA (5). In addition, emergence of drug-resistant virus in patients undergoing long-term maintenance therapy with these drugs has resulted in diminished drug efficacies (12,13).…”

“…1263W94 (5,6,-dichloro-2-isopropylamino-1-␤-L-ribofuranosyl-1H-benzimidazole; Fig. 1) is a member of a new class of drugs, the benzimidazole ribosides and is being developed for the treatment of HCMV.…”

Human Cytomegalovirus: Challenges Opportunities and New Drug Development

“…Foscarnet is approved for intravenous treatment of HCMV retinitis in AIDS patients. Details of the biochemistry, pharmacology, and early clinical use will not be discussed here, but can be found in reviews by Chrisp & Clissold (1991), Haffey & Field (1995) and Pillay et al (1995). In brief, foscarnet is a less potent antiviral drug than ganciclovir 223 Antiviral Chemistry & Chemotherapy 10:5 and renal toxicity may be a major potential side-effect, which is usually manageable by proper hydration.…”

Metal Complexes of Ethane and Propane Frame-Substituted Oligophosphonic and Oligophosphonocarboxylic Acids

“…Arylphosphonates inhibit protein-tyrosine and serine/threonine phosphatases. 13 Phosphonocarboxylates show antiviral properties, 14 inhibit the intestinal and renal phosphate transport 15 as well as the sodium-dependent phosphate reabsorption. 16−18 Bisphosphonates inhibit bone reabsorption and are used as complexing agents for 99m Tc for bone imaging.…”