The antiviral action of vidarabine is completely confined to DNA viruses. Vidarabine inhibits viral DNA synthesis. Enzymes within the cell phosphorylate vidarabine to the triphosphate, which competes with deoxyadenosine triphosphate for viral DNA polymerase. Vidarabine triphosphate is also incorporated into cellular and viral DNA, where it acts as a chain terminator. The triphosphate form of vidarabine also inhibits a set of enzymes that are involved in methyla-tion of uridine to thymidine: ribonucleoside reductase, RNA polyadenylase, and s-adenosylhomocysteine hydrolase.
At one time in the United States, intravenous vidarabine was approved for use against HSV encephalitis, neonatal herpes, and herpes or varicella zoster in immunocompro-mised patients. Acyclovir has supplanted vidarabine as the drug of choice in these cases.
In the treatment of viral encephalitis, vidarabine had to be administered by constant flow intravenous infusion because of its poor water solubility and rapid metabolic conversion to a hypoxanthine derivative in vivo. These problems, coupled with the availability of less toxic and more effective agents, have caused intravenous vidarabine to be withdrawn from the U. S. market.
Vidarabine occurs as a white, crystalline monohydrate that is soluble in water to the extent of 0.45 mg/mL at 25°C. The drug is still available in the United States as a 3% ointment for the treatment of HSV keratitis.
Like idoxuridine, the antiviral mechanism of trifluridine involves inhibition of viral DNA synthesis. Trifluridine monophosphate is an irreversible inhibitor of thymidylate
Adefovir is an orally active prodrug that is indicated for the treatment of the chronic form of hepatitis B. The dipivoxil moieties are hydrolyzed by ubiquitous esterases to yield adefovir, which is phosphorylated by adenylate kinase to yield adefovir diphosphate. This compound is inhibitory at HBV DNA polymerase. In addition, adefovir undergoes incorporation into viral DNA and causes chain termination. Adefovir is poorly absorbed by the oral route, but the dip-ivoxil ester groups cause the bioavailability to increase to approximately 60%.
Acyclovir, 9-[2-(hydroxyethoxy)methyl]-9H-guanine (Zovirax), is the most effective of a series of acyclic nucleosides that possess antiviral activity. In contrast with true nucleosides that have a ribose or a deoxyribose sugar attached to a purine or a pyrimidine base, the group attached to the base in acyclovir is similar to an open chain sugar, albeit lacking in hydroxyl groups. The clinically useful antiviral spectrum of acyclovir is limited to herpesviruses. It is most active (in vitro) against HSV type 1, about two times less against HSV type 2, and 10 times less potent against varicella-zoster virus (VZV). An advantage is that uninfected human cells are unaffected by the drug.
The ultimate effect of acyclovir is the inhibition of viral DNA synthesis. Transport into the cell and monophosphory-lation are accomplished by a thymidine kinase that is encoded by the virus itself.35 The affinity of acyclovir for the viral thymidine kinase is about 200 times that of the corresponding mammalian enzyme. Hence, some selectivity is attained. Enzymes in the infected cell catalyze the conversion of the monophosphate to acyclovir triphosphate, which is present in 40 to 100 times greater concentrations in HSV-infected than uninfected cells. Acyclovir triphosphate competes for endogenous deoxyguanosine triphosphate (dGTP); hence, acyclovir triphosphate competitively inhibits viral DNA polymerases. The triphosphorylated drug is also incorporated into viral DNA, where it acts as a chain terminator. Because it has no 3'-hydroxyl group, no 3',5'-phosphodiester bond can form. This mechanism is essentially a suicide inhibition because the terminated DNA template containing acyclovir as a ligand binds to, and irreversibly inactivates, DNA poly-merase. Resistance to acyclovir can occur, most often by deficient thymidine kinase activity in HSV isolates. Acyclovir resistance in vesicular stomatitis virus (VSV) isolates is caused by mutations in VSV thymidine kinase or, less often, by mutations in viral DNA polymerase.
Two dosage forms of acyclovir are available for systemic use: oral and parenteral. Oral acyclovir is used in the initial treatment of genital herpes and to control mild recurrent episodes. It has been approved for short-term treatment of shingles and chickenpox caused by VZV. Intravenous administration is indicated for initial and recurrent infections in immunocompromised patients and for the prevention and treatment of severe episodes. The drug is absorbed slowly and incompletely from the GI tract, and its oral bioavailability is only 15% to 30%. Nevertheless, acyclovir is distributed to virtually all body compartments. Less than 30% is bound to protein. Most of the drug is excreted unchanged in the urine, about 10% excreted as the carboxy metabolite.
Acyclovir occurs as a chemically stable, white, crystalline solid that is slightly soluble in water. Because of its amphoteric properties (pKa values of 2.27 and 9.25), solubility is increased by both strong acids and bases. The injectable form is the sodium salt, which is supplied as a lyophilized powder, equivalent to 50 mg/mL of active acyclovir dissolved in sterile water for injection. Because the solution is strongly alkaline (pH — 11), it must be administered by slow, constant intravenous infusion to avoid irritation and thrombophlebitis at the injection site.
Adverse reactions are few. Some patients experience occasional GI upset, dizziness, headache, lethargy, and joint pain. An ointment composed of 5% acyclovir in a polyethylene glycol base is available for the treatment of initial, mild episodes of herpes genitalis. The ointment is not an effective preventer of recurrent episodes.
Valacyclovir (Valtrex) is the hydrochloride salt of the l-valyl ester of acyclovir. The compound is a water-soluble crystalline solid, and it is a prodrug intended to increase the bioavailability of acyclovir by increasing lipophilicity. Valacyclovir is hydrolyzed rapidly and almost completely to acyclovir following oral administration. Enzymatic hydrolysis of the prodrug is believed to occur during enterohep-atic cycling. The oral bioavailability of valacyclovir is three to five times that of acyclovir, or about 50%.36
Valacyclovir has been approved for the treatment of herpes zoster (shingles) in immunocompromised patients. The side effect profile observed in valacyclovir is comparable with bioequivalent doses of acyclovir. Less than 1% of an administered dose of valacyclovir is recovered in the urine. Most of the dose is eliminated as acyclovir.
Ganciclovir, 9-[(1,3-dihydroxy-2-propoxy) methyl]guanine) or DHPG (Cytovene), is an analog of acyclovir, with an additional hydroxymethyl group on the acyclic side chain.
This structural modification, while maintaining the activity against HSV and VSV possessed by acyclovir, greatly enhances the activity against CMV infection.
After administration, similar to acyclovir, ganciclovir is phosphorylated inside the cell by a virally encoded protein kinase to the monophosphate.37 Host cell enzymes catalyze the formation of the triphosphate, which reaches more than 10-fold higher concentrations in infected cells than in unin-fected cells. This selectivity is caused by the entry and monophosphorylation step. Further phosphorylation with cellular enzymes occurs, and the triphosphate that is formed selectively inhibits viral DNA polymerase. Ganciclovir triphosphate is also incorporated into viral DNA causing strand breakage and cessation of elongation.38
The clinical usefulness of ganciclovir is limited by the toxicity of the drug. Ganciclovir causes myelosuppression, producing neutropenia, thrombocytopenia, and anemia. These effects are probably associated with inhibition of host cell DNA polymerase.39 Potential central nervous system side effects include headaches, behavioral changes, and convulsions. Ganciclovir is mutagenic, carcinogenic, and teratogenic in animals.
Toxicity limits its therapeutic usefulness to the treatment and suppression of sight-threatening CMV retinitis in im-munocompromised patients and to the prevention of life-threatening CMV infections in at-risk transplant patients.21
Oral and parenteral dosage forms of ganciclovir are available, but oral bioavailability is poor. Only 5% to 10% of an oral dose is absorbed. Intravenous administration is preferable. More than 90% of the unchanged drug is excreted in the urine. Ganciclovir for injection is available as a lyophilized sodium salt for reconstitution in normal saline, 5% dextrose in water, or lactated Ringer solution. These solutions are strongly alkaline (pH —11) and must be administered by slow, constant, intravenous infusion to avoid thrombophlebitis.
Famciclovir is a diacetyl prodrug of penciclovir.40 As a prodrug, it lacks antiviral activity. Penciclovir, 9-[4-hydroxy-3-hydroxymethylbut-1-yl] guanine, is an acyclic guanine
nucleoside analog. The structure is similar to that of acy-clovir, except in penciclovir, a side chain oxygen has been replaced by a carbon atom and an extra hydroxymethyl group is present. Inhibitory concentrations for HSV and VSV are typically within twice that of acyclovir. Penciclovir also inhibits the growth of hepatitis B virus.
Penciclovir inhibits viral DNA synthesis. In HSV- or VSV-infected cells, penciclovir is first phosphorylated by viral thymidine kinase41 and then further elaborated to the triphosphate by host cell kinases. Penciclovir triphosphate is a competitive inhibitor of viral DNA polymerase. The phar-macokinetic parameters of penciclovir are quite different from those of acyclovir. Although penciclovir triphosphate is about 100-fold less potent in inhibiting viral DNA polymerase than acyclovir triphosphate, it is present in the tissues for longer periods and in much higher concentrations than acyclovir. Because it is possible to rotate the side chain of penciclovir into a pseudopentose, the triphosphorylated metabolite possesses a 3'-hydroxy l group. This relationship is shown on page 342 with guanosine. Penciclovir is not an obligate chain terminator,41 but it does competitively inhibit DNA elongation. Penciclovir is excreted mostly unchanged in the urine.
Penciclovir (Denvir) has been approved for the topical treatment of recurrent herpes labialis (cold sores) in adults. It is effective against HSV-1 and HSV-2.42 It is available as a cream containing 10% penciclovir.
Cidofovir, (S)-3-hydroxy-2-phosphonomethoxypropyl cyto-sine (HPMPC, Vistide), is an acyclonucleotide analog that possesses broad-spectrum activity against several DNA viruses. Unlike other nucleotide analogs that are activated to nucleoside phosphates, Cidofovir is a phosphonic acid derivative. The phosphonic acid is not hydrolyzed by phosphatases in vivo but is phosphorylated by cellular kinases to yield a diphosphate. The diphosphate acts as an antimetabolite to de-oxycytosine triphosphate (dCTP). Cidofovir diphosphate is a competitive inhibitor of viral DNA43 polymerase and can be incorporated into the growing viral DNA strand, causing DNA chain termination.
Cidofovir possesses a high therapeutic index against CMV and has been approved for treating CMV retinitis in patients with AIDS. Cidofovir is administered by slow, constant intravenous infusion in a dose of 5 mg/kg over a 1-hour period once a week for 2 weeks. This treatment is followed by a maintenance dose every 2 weeks. About 80% of a dose of Cidofovir is excreted unchanged in the urine, with a t1/2elim of 2 to 3 hours. The diphosphate antimetabolite, in contrast, has an extremely long half-life (17-30 hours).
The main dose-limiting toxicity of cidofovir involves renal impairment. Renal function must be monitored closely. Pretreatment with probenecid and prehydration with intravenous normal saline can be used to reduce the nephrotoxicity of the drug. Patients must be advised that cidofovir is not a cure for CMV retinitis. The disease may progress during or following treatment.
Trisodium phosphonoformate is an inorganic pyrophosphate analog that inhibits replication in herpesviruses (CMV, HSV, and VSV) and retroviruses (HIV).44 Foscarnet (Foscavir) is taken up slowly by the cells and does not undergo significant intracellular metabolism. Foscarnet is a reversible, noncompetitive inhibitor at the pyrophosphate-binding site of the viral DNA polymerase and RT. The ultimate effect is inhibition of the cleavage of pyrophosphate from deoxynucleotide triphosphates and a cessation of the incorporation of nucleoside triphosphates into DNA (with the concomitant release of pyrophosphate).45 Because the inhibition is noncompetitive with respect to nucleoside triphosphate binding, foscarnet can act synergistically with nucleoside triphosphate antimetabolites (e.g., zidovudine and didanosine triphosphates) in the inhibition of viral DNA synthesis. Foscarnet does not require bioactivation by viral or cellular enzymes and, hence, can be effective against resistant viral strains that are deficient in virally encoded nucleoside kinases.45
Foscarnet is a second-line drug for the treatment of retinitis caused by CMV in patients with AIDS. The drug causes metabolic abnormalities including increases or decreases in blood Ca2+ levels. Nephrotoxicity is common, and this side effect precludes the use of foscarnet in other infections caused by herpesvirus or as single-agent therapy for HIV infection. Foscarnet is an excellent ligand for metal ion binding, which undoubtedly contributes to the electrolyte imbalances observed with the use of the drug.46 Hypocalcemia, hypomag-nesemia, hypokalemia, and hypophosphatemia and hyper-phosphatemia are observed in patients treated with foscarnet. Side effects such as paresthesias, tetani, seizures, and cardiac arrhythmias may result. Because foscarnet is nephrotoxic, it may augment the toxic effects of other nephrotoxic drugs, such as amphotericin B and pentamidine, which are frequently used to control opportunistic infections in patients with AIDS.
Foscarnet sodium is available as a sterile solution intended for slow intravenous infusion. The solution is compatible with normal saline and 5% dextrose in water but is incompatible with calcium-containing buffers such as lactated Ringer solution and total parenteral nutrition (TPN) preparations. Foscarnet reacts chemically with acid salts such as midazolam, vancomycin, and pentamidine. Over 80% of an injected dose of foscarnet is excreted unchanged in the urine.44 The long elimination half-life of foscarnet is thought to result from its reversible sequestration into bone.46
An early event in the replication of HIV-1 is reverse transcription, whereby genomic RNA from the virus is converted into a cDNA-RNA complex, then into double-stranded DNA ready for integration into the host chromosome. The enzyme that catalyzes this set of reactions is reverse tran-
scriptase. RT actually operates twice prior to the integration step. Its first function is the creation of the cDNA-RNA complex; RT acts alone in this step. In the second step, the RNA chain is digested away by RNase H, whereas RT creates the double-stranded unintegrated DNA.
All of the classical antiretroviral agents are 2',3'-dideoxynucleoside analogs. These compounds share a common mechanism of action in inhibiting the RT of HIV. Because RT acts early in the viral infection sequence, inhibitors of the enzyme block acute infection of cells but are only weakly active in chronically infected ones. Even though the RT inhibitors share a common mechanism of action, their pharmacological and toxicological profiles differ dramatically.
Zidovudine, 3'-azido-3'-deoxythymidine or AZT, is an analog of thymidine that possesses antiviral activity against HIV-1, HIV-2, HTLV-1, and several other retroviruses. This nucleoside was synthesized in 1978 by Lin and Prusoff47 as an intermediate in the preparation of amino acid analogs of thymidine. A screening program directed toward the identification of agents potentially effective for the treatment of patients with AIDS led to the discovery of its unique antiviral properties 7 years later.48 The next year, the clinical effectiveness of AZT in patients with AIDS and AIDS-related complex (ARC) was demon-strated.49 AZT is active against retroviruses, a group of RNA viruses responsible for AIDS and some kinds of leukemia. Retroviruses possess a RT or an RNA-directed DNA polymerase that directs the synthesis of a DNA copy (proviral DNA) of the viral RNA genome that is duplicated, circularized, and incorporated into the DNA of an infected cell. The drug enters the host cells by diffusion and is phosphorylated by cellular thymidine kinase. Thymidylate kinase then converts the monophosphate into diphosphates and triphosphates. The rate-determining step is conversion to the diphosphate, so high levels of monophosphorylated AZT accumulate in the cell. Low levels of diphosphate and triphosphate are present. Zidovudine triphosphate competitively inhibits RT with respect to thymidine triphosphate. The 3'-azido group prevents formation of a 5',3'-phosphodiester bond, so AZT causes DNA chain termination, yielding an incomplete proviral DNA.50 Zidovudine monophosphate also competitively inhibits cellular thymidylate kinase, thus decreasing intracellular levels of thymidine triphosphate. The antiviral selectivity of AZT is caused by its greater (100X)51 affinity for HIV RT than for human DNA polymerases. The human y-DNA polymerase of mitochondria is more sensitive to zidovudine; this may contribute to the toxicity associated with the drug's use. Resistance is common and is a result of point mutations at multiple sites in RT, leading to a lower affinity for the drug.52
Zidovudine is recommended for the management of adult patients with symptomatic HIV infection (AIDS or ARC) who have a history of confirmed Pneumocystis carinii pneumonia or an absolute CD4+ (T4 or TH cell) lymphocyte count below 200/mm3 before therapy. The hematological toxicity of the drug precludes its use in asymptomatic patients. Anemia and granulocytopenia are the most common toxic effects associated with AZT.
For oral administration, AZT is supplied as 100-mg capsules and as a syrup containing 10 mg AZT per mL. The injectable form of AZT contains 10 mg/mL and is injected intravenously. AZT is absorbed rapidly from the GI tract and distributes well into body compartments, including the cerebrospinal fluid (CSF). It is metabolized rapidly to an inactive glucuronide in the liver. Only about 15% is excreted unchanged. Because AZT is an aliphatic azide, it is heat and light sensitive. It should be protected from light and stored at 15°C to 25°C.
Didanosine (Videx, ddI) is 2',3'-dideoxyinosine (ddI), a synthetic purine nucleoside analog that is bioactivated to 2' ,3'-dideoxy-ATP (ddATP) by host cellular enzymes.53 The metabolite, ddATP, accumulates intracel-lularly, where it inhibits RT and is incorporated into viral DNA to cause chain termination in HIV-infected cells. The potency of didanosine is 10- to 100-fold less than that of AZT with respect to antiviral activity and cytotoxicity, but the drug causes less myelosuppression than AZT causes.54
Didanosine is recommended for the treatment of patients with advanced HIV infection who have received prolonged treatment with AZT but have become intolerant to, or experienced immunosuppression from, the drug. AZT and ddI act synergistically to inhibit HIV replication in vitro, and ddI is effective against some AZT-resistant strains of HIV.55 Painful peripheral neuropathy (tingling, numbness, and pain in the hands and feet) and pancreatitis (nausea, abdominal pain, elevated amylase) are the major dose-limiting toxicities of didanosine. Didanosine is given orally in the form of buffered chewable tablets or as a solution prepared from the powder. Both oral dosage forms are buffered to prevent acidic decomposition of ddI to hypoxanthine in the stomach. Despite the buffering of the dosage forms, oral bioavailabil-ity is quite low and highly variable. Less than 20% of a dose is excreted in the urine, which suggests extensive metabolism.56 Food interferes with absorption, so the oral drug must be given at least 1 hour before or 2 hours after meals. High-dose therapy can cause hyperuricemia in some patients because of the increased purine load.
Zalcitabine, 2',3'-dideoxycytidine or ddCyd, is an analog of cytosine that demonstrates activity against HIV-1 and HIV-2, including strains resistant to AZT. The potency (in peripheral blood mononuclear cells) is similar to that of AZT, but the drug is more active in populations of monocytes and macrophages as well as in resting cells.
Zalcitabine enters human cells by carrier-facilitated diffusion and undergoes initial phosphorylation by deoxycyti-dine kinase. The monophosphorylated compound is further metabolized to the active metabolite, dideoxycytidine-5'-triphosphate (ddCTP), by cellular kinases.57 ddCTP inhibits RT by competitive inhibition with dCTP. Most likely, ddCTP causes termination of the elongating viral DNA chain.
Zalcitabine inhibits host mitochondrial DNA synthesis at low concentrations. This effect may contribute to its clinical toxicity.58
The oral bioavailability of zalcitabine is over 80% in adults and less in children.59 The major dose-limiting side effect is peripheral neuropathy, characterized by pain, paresthesias, and hypesthesia, beginning in the distal lower extremities. These side effects are typically evident after several months of therapy with zalcitabine. A potentially fatal pancreatitis is another toxic effect of treatment with ddC. The drug has been approved for the treatment of HIV infection in adults with advanced disease who are intolerant to AZT or who have disease progression while receiving AZT. ddC is combined with AZT for the treatment of advanced HIV infection.
Stavudine, 2'3'-didehydro-2'-deoxythymidine (D4T, Zerit), is an unsaturated pyrimidine nucleoside that is related to thymidine. The drug inhibits the replication of HIV by a mechanism similar to that of its close congener, AZT.60 Stavudine is bioac-tivated by cellular enzymes to a triphosphate. The triphosphate competitively inhibits the incorporation of thymidine triphosphate (TTP) into retroviral DNA by RT.61 Stavudine also causes termination of viral DNA elongation through its incorporation into DNA.
Stavudine is available as capsules for oral administration. The drug is acid stable and well absorbed (about 90%) following oral administration. Stavudine has a short half-life (1-2 hours) in plasma and is excreted largely unchanged (85%-90%) in the urine.62 As with ddC, the primary dose-limiting effect is peripheral neuropathy. At the recommended dosages, approximately 15% to 20% of patients ex perience symptoms of peripheral neuropathy. Stavudine is recommended for the treatment of adults with advanced HIV infection who are intolerant of other approved therapies or who have experienced clinical or immunological deterioration while receiving these therapies.
Abacavir is a nucleoside reverse transcriptase inhibitor NRTI that has been approved for use in combination therapies for the treatment of HIV and AIDS. Once in the tissues, it is metabolized by stepwise phosphorylation to the monophosphate, diphosphate, and triphosphate. Abacavir is highly bioavailable (>75%) and is effective by the oral route. It penetrates the blood-brain barrier efficiently. Abacavir has been reported to produce life-threatening hypersensitivity reactions in some patients.
Tenofovir disoproxil is a prodrug analogously with abacavir. Plasma and tissue esterases cleave the phosphate protecting groups, releasing the active drug. The bioavailability of tenofovir is about 35% when administered with food. The drug is approved by the Food and Drug Administration (FDA) for the treatment of HIV infections in adult patients. Recommendations are for the drug to be administered with other RT inhibitors or PIs to achieve synergism.
Lamivudine is ( — )-2',3'-dideoxy-3'-thiacytidine, (-)-fi-L-(2r,5s)-1,3-oxathiolanylcytosine, 3TC, or (—)-(s)-ddC. Lamivudine is a synthetic nucleoside analog that differs from 2',3'-dideoxycytidine (ddC) by the substitution of a sulfur atom in place of a methylene group at the 3'-position of the ribose ring. In early clinical trials, lamivudine exhibited highly promising antiretroviral activity against HIV and low toxicity in the dosages studied.63,64 Preliminary pharmacokinetic studies indicated that it exhibited good oral bioavailability (F = —80%) and a plasma half-life of 2 to 4 hours.63
It is interesting that the unnatural stereoisomer ( — )-(S)-ddC exhibits greater antiviral activity against HIV than the natural enantiomer ( + )-(s)-ddC.65 Both enantiomers are bioactivated by cellular kinases to the corresponding triphosphates.66 Both SddCTP isomers inhibit HIV RT and are incorporated into viral DNA to cause chain termination. ( + )-s-ddCTP inhibits cellular DNA polymerases much more strongly than ( — )-SddCTP, explaining the greater toxicity associated with ( + )-(s)-ddC. Initial metabolic comparison of SddCTP isomers has failed to explain the greater potency of the ( — )-isomer against HIV. Therefore, although the intracellular accumulation of (— )-s-ddCTP was twice that of (+)-s-ddCTP, the latter was one and a half times more potent as an inhibitor of HIV RT, and the two isomers were incorporated into viral DNA at comparable rates. The puzzle was solved with the discovery of a cellular 3',5'-exonuclease, which was found to cleave terminal ( + )-s-ddCMP incorporated into viral DNA 6 times faster than ( — )-s-ddCMP from the viral DNA terminus.
Resistance to lamivudine develops rapidly as a result of a mutation in codon 184 of the gene that encodes HIV-RT when the drug is used as monotherapy for HIV infection.64 When combined with AZT, however, lamivudine caused substantial increases in CD4+ counts. The elevated counts were sustained over the course of therapy.67 The codon mutation that causes resistance to lamivudine suppresses AZT resistance,67 thus increasing the susceptibility of the virus to the drug combination.
Emtricitabine is an orally active NRTI whose pharmacoki-netics are favorable for once-daily administration.
Miscellaneous Nucleoside Antimetabolites
Ribavirin is 1-jß-d-ribofuranosyl-1,2,4-thiazole-3-carbox-amide. The compound is a purine nucleoside analog with a modified base and a d-ribose sugar moiety.
Ribavirin inhibits the replication of a very wide variety of RNA and DNA viruses,68 including orthomyxoviruses, paramyxoviruses, arenaviruses, bunyaviruses, herpesviruses, adenoviruses, poxvirus, vaccinia, influenza virus (types A and B), parainfluenza virus, and rhinovirus. In spite of the broad spectrum of activity of ribavirin, the drug has been approved for only one therapeutic indication—the treatment of severe lower respiratory infections caused by RSV in carefully selected hospitalized infants and young children.
The mechanism of action of ribavirin is not known. The broad antiviral spectrum of ribavirin, however, suggests multiple modes of action.69 The nucleoside is bioactivated by viral and host cellular kinases to give the monophosphate (RMP) and the triphosphate (RTP). RMP inhibits inosine monophosphate (IMP) dehydrogenase, thereby preventing the conversion of IMP to xanthine monophosphate (XMP). XMP is required for guanosine triphosphate (GTP) synthesis. RTP inhibits viral RNA polymerases. It also prevents the end capping of viral mRNA by inhibiting guanyl-N'-methyltransferase. Emergence of viral resistance to ribavirin has not been documented.
Ribavirin occurs as a white, crystalline, polymorphic solid that is soluble in water and chemically stable. It is supplied as a powder to be reconstituted in an aqueous aerosol containing 20 mg/mL of sterile water. The aerosol is administered with a small-particle aerosol generator (SPAG). Deterioration in respiratory function, bacterial pneumonia, pneumothorax, and apnea have been reported in severely ill infants and children with RSV infection. The role of ribavirin in these events has not been determined. Anemia, headache, abdominal pain, and lethargy have been reported in patients receiving oral ribavirin.
Unlabeled uses of ribavirin include aerosol treatment of influenza types A and B and oral treatment of hepatitis, genital herpes, and Lassa fever. Ribavirin does not protect cells against the cytotoxic effects of the AIDS virus.
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