Purine Nucleosides Used in Animals

Acyclovir (acycloguanosine) and its l-valyl ester prodrug valacyclovir represent a new generation of antiviral agents, mainly because of the unique mechanism of action. Acyclovir is a member of a class of acyclic nucleoside analogues characterized by requiring three phosphorylation steps for activation. The first step in this process is most effectively catalyzed by viral thymidine kinase, and the efficiency with which the virus completes this first step is key to the efficacy of this class of antiviral agents. Because the first step of phosphorylation is catalyzed by viral, rather than host, thymidine kinase, acyclovir is considered relatively safe for systemic administration. Once activated to the triphosphate form, acyclovir is a better substrate and inhibitor of viral, versus host, DNA polymerase. Binding to DNA polymerase is irreversible, and once acyclovir is incorporated into viral DNA, the DNA chain is terminated.

Acyclovir is relatively safe (coadministration of probenecid renders the drug safer) and is useful against a variety of infections caused by DNA viruses, especially those in the herpesvirus family. However, resistance is increasing. Acyclovir is unable to eliminate latent infections, and it has been noted to be relatively ineffective and to have low potency against feline herpesvirus 1 (FHV-1). In addition, acyclovir has relatively low bioavailability in cats, and systemic administration can cause bone marrow suppression in this species. Therefore, systemic administration is not recommended in cats. Indications or appropriate doses for use of acyclovir have not been established in dogs.

Acyclovir has been used in the treatment and prevention of equine herpesvirus myeloencephalopathy (EHM). The oral bioavailability of a single dose of acyclovir is poor in horses, but the drug's long elimination half-life suggests appreciable drug accumulation and higher serum concentrations may occur with many months of oral dosing.1 However, the low single-dose bioavailability, marked interpatient variability, and requirement of multiple days to reach effective plasma concentrations give orally administered acyclovir limited clinical utility in the face of an EHM outbreak. Intravenous administration of acyclovir improves the pharmacokinetic deficiencies of the oral formulation in horses; however, the high cost, the short duration of therapeutic plasma concentrations, and the need to administer the drug as a constant-rate infusion over 1 hour to minimize toxicity present challenges. Therefore, IV use of acyclovir has not been reported in clinical cases of EHM or EHV-1.

Adverse effects after oral or IV administration of acyclovir in horses are infrequently reported. Acyclovir has also been used to treat pulmonary disease secondary to equine herpesvirus 1 (EHV-1) infection in foals, as well as equine multinodular pulmonary fibrosis (EMPF) secondary to EHV-5 infection in horses, without definitive evidence of efficacy.

Acyclovir is known to cause nephrotoxicosis and neurotoxicosis following parenteral administration. Nephrotoxicosis results when the precipitation of acyclovir crystals in the renal tubules leads to an obstructive nephropathy. Contributing factors include preexisting renal insufficiency, rapid IV bolus administration, high dose administration, and concomitant administration of other nephrotoxic agents.

Acyclovir is available as an ophthalmic ointment (outside of the US), a topical ointment and cream, an IV preparation, and various oral formulations. Application of 0.5% acyclovir ophthalmic ointment 5 times daily has been shown to be effective in the treatment of ocular disease due to FHV-1 in cats, but at 3 times daily this preparation was not effective. Topical acyclovir was found to be no better than placebo in the treatment of equine sarcoids. There are currently no ophthalmic acyclovir formulations approved for use in the US. Topical formulations of acyclovir approved in the US are not suitable for ophthalmic administration, and therefore ophthalmic specific preparations must be compounded. The prodrug deoxyacyclovir is more readily absorbed from the GI tract than acyclovir is.

Another similar antiviral purine nucleoside analogue is ganciclovir, a synthetic guanine effective against human cytomegalovirus. Its mechanism of action is similar to that of acyclovir. Ganciclovir is available as an IV preparation and as an ophthalmic preparation. Ganciclovir (0.15% ophthalmic solution, 1 drop in the affected eye, 5 times daily until the ulcer has healed and then 1 drop, 3 times daily for 7 more days) has been found to be experimentally effective in the treatment of ocular canine herpesvirus 1 with decreased viral shedding and clinical improvement and no evidence of adverse effects. Ganciclovir is highly inhibitory to FHV-1 in vitro; however, no pharmacokinetic, safety, or efficacy studies have been performed in vivo. Ganciclovir has been found to achieve concentrations suitable for EHV-1 inhibition in horses when administered at 2.5 mg/kg, IV, every 8 hours for 1 day, then every 12 hours for 1 week as a slow IV bolus. Note, however, that ganciclovir has been associated with a high rate of adverse effects after systemic use in humans, resulting in cytopenias and neurotoxicosis.

Amantadine and its derivative rimantadine are synthetic antiviral agents that appear to act on an early step of viral replication after attachment of the virus to cell receptors. The effect seems to lead to inhibition or delay of the uncoating process that precedes primary transcription. Amantadine may also interfere with the early stages of viral mRNA transcription. Amantadine at usual concentrations inhibits the replication of different strains of influenza A virus, influenza C virus, Sendai virus, and pseudorabies virus. It is almost completely absorbed from the GI tract, and ~90% of a dose administered orally is excreted unchanged in the urine over several days (human data).1 The main clinical use of amantadine has been to prevent infection with various strains of influenza A viruses In vitro, amantadine has been shown to suppress equine influenza virus replication at plasma concentrations of 300 ng/mL, while its more potent derivative rimantadine suppresses viral replication at 30 ng/mL.2 Amantadine is only available in oral formulations in the US.

When administered IV to horses, doses of 15 mg/kg may lead to fatal seizures that occur without warning, and lowering the dose to 10 mg/kg may still lead to seizures in individuals with a low seizure threshold. In humans, rare instances of irreversible hepatic enzyme elevation have been reported with use of amantadine, but not rimantadine.

Marked individual variation has been noted in the bioavailability of the oral formulation in horses, making it impossible to determine appropriate dosing without therapeutic drug monitoring. Rimantadine demonstrated more stable pharmacokinetics when administered orally to horses (30 mg/kg, PO, every 12 hours), with no adverse effects noted.3Prophylactic use of rimantadine led to an appreciable decrease in rectal temperature and pulmonary sounds, compared with placebo, during an influenza A2 challenge study in horses.3 Amantadine has been used extensively for its NMDA receptor antagonist properties in the management of chronic pain in both large and small animals.

In 2006, the FDA prohibited extralabel use of the adamantane and neuraminidase inhibitor classes in chickens, turkeys, and ducks because of the potential emergence of resistant strains of influenza A, including H5N1 avian influenza virus in the human population. Resistance to adamantane antivirals has been documented in influenza A strains in humans and poultry. Although extralabel drug use (ELDU) is not prohibited in other species, these antivirals should be considered to be reserved classes of drugs to preserve their efficacy in the human population, should not be used in food animals, and should be used only in instances of documented infection and only when other agents or measures are considered inadequate for patient survival.

Cidofovir, is used topically for ocular herpesvirus in cats. This drug is a nucleoside monophosphate cysteine analog that is a competitive inhibitor of viral DNA polymerases and thus DNA synthesis. In general, cidofovir has broader activity against a variety of DNA viruses compared to other drugs in the nucleoside class. Additionally, since cidofovir accumulates intracellularly, it is able to be administered less frequently due to a longer elimination half-life. It is nonselective in its mechanism of action, and therefore significant side effects prevent systemic administration. When administered systemically, cidofovir can cause nephrotoxicity. While an ophthalmic formulation is not currently available, 0.5% ophthalmic solution compounded from the injectable formulation has been used in cats with ocular disease secondary to feline herpesvirus 1 (FHV-1) infection.

Penciclovir is very similar to acyclovir in terms of mechanism of action and spectrum. Unlike acyclovir, however, penciclovir has been shown to be highly effective against feline herpesvirus 1 (FHV-1) in vitro and in vivo. Although it is much less potent than acyclovir, penciclovir accumulates to much higher concentrations inside the cell. Penciclovir is available as only a topical ointment, and ophthalmic use of the topical preparation is not recommended. Penciclovir pharmacokinetics and in vitro efficacy against equine herpesvirus 1 (EHV-1) have been studied in horses; however, safety and efficacy studies have not been performed in vivo, and no dosage has been established.

Famciclovir is the prodrug form of penciclovir. The metabolism of famciclovir to penciclovir is multifaceted and complex in humans. The pharmacokinetics of famciclovir have been studied in cats, and the drug was found to have nonlinear kinetics suspected to be a result of saturation of the hepatic oxidation step in its metabolism. This variability in pharmacokinetics has led to a wide range of dose recommendations for cats. Dosing at 90 mg/kg, PO, every 12 hours, has been reported to be effective for the treatment of FHV-1.1 Famciclovir appears to be much safer than acyclovir and valacyclovir in cats. However, caution should be taken and the dose decreased in cats with renal insufficiency, and routine blood work should be monitored for all patients. Famciclovir pharmacokinetics have been described in dogs; however, indications, dosage, safety, and efficacy have not been established in this species.

Valacyclovir is the L-valyl ester prodrug of acyclovir that was developed to improve the bioavailability of acyclovir by providing a substrate for carrier-mediated transport into enterocytes. After being absorbed, valacyclovir is converted to acyclovir via hepatic hydrolase.

Because of its mutagenic potential, valacyclovir is not recommended for use in food-producing animals. Like acyclovir, valacyclovir has been reported to cause nephrotoxicosis and bone marrow suppression. In addition, because it undergoes hepatic metabolism to acyclovir, hepatotoxicity has also been reported. Valacyclovir should never be administered to cats, because bone marrow suppression and potentially fatal hepatic and renal necrosis after systemic administration have been reported. Furthermore, because feline herpesvirus 1 (FHV-1) is considered resistant to acyclovir and valacyclovir, these drugs are not considered clinically useful in cats.

In horses, valacyclovir (27–40 mg/kg, every 8 hours, for 2 days; then 18–20 mg/kg, every 8 hours, for 1–2 weeks) has been used preferentially in the treatment and prevention of equine herpesvirus myeloencephalopathy (EHM) because of its improved bioavailability. Valacyclovir has been shown to decrease viral shedding, rectal temperature, viremia, and severity of ataxia when administered prophylactically to horses before equine herpesvirus 1 (EHV-1) challenge. When administered after EHV-1 challenge, valacyclovir was still noted to decrease the severity of clinical signs, compared with placebo. Adverse effects are infrequently reported in horses when the drug is administered at recommended doses. Valacyclovir is available solely in tablet form.

Vidarabine, or Ara-A, is used topically for ocular herpesvirus and systemically for herpetic encephalitis and neonatal herpesviral infections. This drug is an adenosine derivative that is phosphorylated by cellular enzymes to a triphosphate compound that inhibits many viral and human DNA polymerases and thus DNA synthesis. Herpesviral enzymes are ~20 times as susceptible to the drug as host DNA is. It is nonselective in its mechanism of action, so its toxicity to the host is notable, particularly after systemic administration. It may produce bone marrow suppression and adverse CNS effects when high blood concentrations are reached. An ophthalmic solution of vidarabine also is available, which is better tolerated than other nucleoside analogues (eg, idoxuridine) and has been used in cats with ocular disease secondary to feline herpesvirus 1 (FHV-1).

Zidovudine (azidothymidine, commonly known as AZT) is a thymidine analogue. Within the virus-infected cell, the 3′-azido group is used by retroviral reverse transcriptase and incorporated into DNA transcription, preventing viral replication. The shared mechanism of action is inhibition of RNA-dependent DNA polymerase (reverse transcriptase). Reverse transcriptase converts the viral RNA genome into double-stranded DNA before it is integrated into the cell genome. Because these actions occur early in replication, AZT tends to be effective for acute infections; however, it is relatively ineffective for chronically infected cells. Cellular alpha-DNA polymerases are inhibited only at concentrations 100-fold as great as those necessary to inhibit reverse transcriptase, thus rendering AZT relatively safe to host cells. Cellular gamma-DNA polymerase, however, is inhibited at lower concentrations.

Zidovudine is effective against a variety of retroviruses at low concentrations. Resistance to AZT is associated with point mutations resulting in amino acid substitutions in the reverse transcriptase. Prolonged use of AZT can facilitate viral resistance. The risk of resistance also appears to correlate with CD4 cell count and the state of infection. Viral susceptibility to AZT may return after the drug has been discontinued for a period of time.

Granulocytopenia and anemia are the major adverse effects of AZT in human patients. The risk of toxicosis increases in human patients with low lymphocyte (CD4-positive T lymphocyte) counts, high doses, and prolonged treatment. Granulocyte colony-stimulating factor is indicated to manage granulocytopenia. Central nervous system adverse effects are more likely as treatment begins. The risk of bone marrow suppression is increased by drugs that inhibit glucuronidation or renal excretion and may be increased in cats.

After a single dose of AZT at 25 mg/kg in cats by intragastric and oral routes, bioavailability is ~75%–100%.1 The elimination half-life is ~1.5 hours, and the volume of distribution is 0.82 L/kg. Drug concentrations remain above the half maximal effective concentration (EC₅₀) of 0.19 mcg/mL for feline immunodeficiency virus (FIV) for at least 24 hours after either IV or oral administration. Although this concentration is higher than that associated with myeloid suppression of human cells, adverse effects in cats are limited to transient restlessness, mild anxiety, and hemolysis.

Studies in cats regarding the efficacy of AZT (5-10 mg/kg, every 12 hours for 42 days) for feline leukemia virus (FeLV) infection indicated that AZT prevents retroviral infection if administered immediately after viral exposure and may decrease replication if administered to previously infected animals. Serum-neutralizing antibodies developed in some of the infected cats, and the cats became resistant to subsequent viral challenge. There was no altered progression of disease in cats when treatment was withheld until 28 days after infection, but the amount of viremia was much lower than in untreated cats. However, these effects have not been replicated in cats with naturally occurring FeLV. In a study, AZT appeared to be nontoxic in uninfected cats; however, 3 of 12 infected kittens develop anorexia and icterus and were vomiting after 40 days of treatment.2 Zidovudine may cause Heinz body anemia. Serial CBCs should be performed on cats receiving AZT. Minimal pharmacokinetic studies have been performed in dogs. No pharmacokinetic, efficacy, or safety studies have been reported in other veterinary species.