Picornaviridae -- polioviruses (poliomyelitis), coxsackieviruses and echoviruses (aseptic meningitis), and rhinoviruses (common cold)
Reoviridae -- rotaviruses (diarrhea)
Togaviridae -- various mosquito-borne encephalitis viruses (encephalitis), yellow fever virus (yellow fever), and rubella virus (rubella)
Orthomyxoviridae -- influenza viruses (influenza)
Paramyxoviridae -- parainfluenza viruses (croup, pneumonia, bronchitis), mumps virus (mumps), measles virus (measles), and respiratory syncytial virus (bronchiolitis, pneumonia)
Rhabdoviridae -- rabies virus (rabies)
Coronaviridae -- coronoviruses (respiratory illnesses)
Bunyaviridae -- California encephalitis viruses (encephalitis)
Retroviridae -- human T-cell lymphotropic viruses (leukemia / lymphoma; HTLV-1, HTLV-II), human immunodeficiency virus types 1 and 2 (HIV-1, HIV-2) (acquired immunodeficiency syndrome)
Papovaviridae -- papilloma viruses (warts, progressive multifocal leukoencephalopathy)
Adenoviridae -- adenoviruses (acute respiratory diseases, keratitis)
Herpesviridae -- herpes simplex types 1 and 2 ("cold" sores, keratitis, genital infections, encephalitis), varicella-zoster (chickenpox, shingles), cytomegalovirus (cytomegalic inclusion disease, chorioretinitis, pneumonitis), Epstein-Barr virus (infectious mononucleosis, association with Burkitt's lymphoma), and human herpesvirus type 6 and 7 (unknown disease association)
Chordopoxviridae -- variola virus (smallpox)
Viruses capable of transforming cells include: adenoviruses, papovaviruses, retroviruses, herpesviruses
Most viral infections acute. Examples of chronic viral infections include: hepatitis B and non-A/non-B, warts, molluscum contagiosum.
· AMADE90,5:2
HSV - herpes simplex virus
VZV - Varicella-Zoster Virus
CMV - Cytomegalovirus
Most of viral replication may be completed by time disease signs show, especially in acute infections
Much of viral life cycle depends on normal host cellular constituents or on enzymes that resemble host counterparts.
Some processes unique to viruses are being found
symptomatic and supportive, especially for respiratory infections
Example: bed rest, analgesics, antipyretics
Examples:
Can be produced by repeated passage in culture
Has been reported for idoxuridine, vidarabine, cytarabine, trifluorothymidine, acyclovir, ganciclovir, zidovudine, BVDU, FIAC, PAA, and PFA.
Cross-resistance due to TK-mutants reported for idoxuridine, cytarabine, acyclovir, and BVDU.
Cross-resistance due to changes in DNA polymerase have been described, but are not well defined. Regions of genome that map resistance to various drugs are being defined.
None
Acyclovir [Zovirax]
Ribavarin [Virazole]
Vidarabine [Ara-A]
Idoxuridine [Herplex, Stoxil]
Fluridine [Viroptic]
Dihydroxy propoxymethyl guanine [DHPG]
Amantadine [Symmetrel]
Zidovudine [Retrovir, AZT, Azidothymidine]
Highly selective inhibition of influenza A viruses (H1 N1, H2 N2, and H3 N2). NOT clinically active versus influenza B viruses.
Used prophylactically in midst of influenza A epidemic.
Tricyclic amine
Two main actions
Blocks ion channel! In Parkinson's, blocks nicotinic cholinergic receptor. In virus, blocks acidification of virus core via the M2 protein ion channel. Acidification is important during aDsorption and penetration of virus into cells via endosomes. This mechanism predominates in hyman influenza virus strains.
Also indirectly blocks late stage Influenza A virus assembly at 0.4 ug/ml, by affecting the conformation of hemagglutinin during virus assembly. This mechanism predominates in avian myxovirus strains.
Dissociation to matrix protein and release of RNA into infected cell cytoplasm is thought to depend on an indirect conformation change in hemagglutinin followed by acidification of the virus core.
Requires higher concentrations for influenza B, rubella, and other viruses so clinical efficacy is questionable to absent.
Can create resistant strains by serial passage
Used PO, well absorbed to give peak plasma concentration of 0.3 to 0.6 ug/ml after 200 mg dose (70 kg man)
Eliminated unchanged in urine
Adverse Effects above 1-5 ug/ml
* CNS toxicity, (1-5% patients / normal renal function) nervousness, confusion, hallucinations, seizures, and coma
Prophylactically at 200 mg/day --> 70-80% effective in influenza A infections
Prophylactically at 100 mg/day --> reported to protect children and elderly.
Therapeutically, accelerates recovery from acute signs and fever in influenza A.
Main problem in use, is being certain infection is influenza A!
Widely used in Parkinson's disease
Used successfully in experimental infections in turkeys and horses (Brander91)
RIMANTIDINE is related drug with spectrum and MOA identical to amantadine. May be less adverse effects.
AMADE90,5:10 5:11. major reference
NONE
nucleoside derivatives
Acyclic purine nucleoside analogue of guanosine
Best example of selective antiviral drug! i.e., relatively large safety margin
Essentially only for herpes viruses (especially H.simplex type 1, 0.02 to 0.2 ug/ml; for type 2, 0.03 to 0.5 ug/ml)
Activated by herpesvirus thymidine kinase (binds 200 times more strongly and phosphorylates 3 million times faster than does host thymidine kinase): acyclovir to acyclovir monophosphate, a nucleoside. Rate of conversion 30 to 120 times faster in infected cells than non-infected cells. Activation occurs primarily in infected cells.
Monophosphate derivative converted to diphosphate by cellular guanylate kinase.
Diphosphate converted to triphosphate (acyclo-GTP) by several cellular enzymes.
Acyclo-GTP derivative is a relatively specific inhibitor of viral DNA polymerase compared to its efect on host DNA polymerase.
Acyclovir can be incorporated into DNA chain more by viral DNA polymerase than by host polymerase giving another level of selectivity. Because no 3'-hydroxyl, this terminates chain elongation. Terminated chain strongly binds and inactivates viral DNA polymerase.
Has been given to humans both IV and PO.
Widely distributed, including CSF
Probenecid increases half-life by 20%
Few side effects in humans other than nausea with PO administration and irritation in tissues when drug is extravasated.
Rx of choice herpes simplex encephalitis (mortality rate 13% at one month, 19% at six months, 28% overall; for vidarabine, numbers were - 43%, 54%, 54%).
In immunocompetent patients, oral acyclovir effective in primary herpes genitalis, but does not reduce rate of asymptomatic viral shedding. Herpes labialis, reduces pain and healing time, but not affect new lesion development.
PO and IV acyclovir reduce pain and accelerate healing in herpes zoster. PO form now aproved for varicella-zoster infections in immunocompetent pats.; IV form for varicella-zoster infections in immunocompromised adults and children.
Topical acyclovir efficacious for mucocutaneous herpesvirus infections in immunocompromised pats, but not in many immunocompetent patients. Topical application May be more useful for primary genital herpes infections than recurrent. However oral adm is superior.
Topical efffective herpes simplex keratitis.
AMADE90,5:7
acyclic nucleoside analog of acyclovir (3-D structure by X-ray crystallography resembles guanosine)
More activity vs CMV than acyclovir
Pro-drug activated by virus-induced kinase (not thymidine kinase) to monophosphate.
Subsequent activation to di and triphosphate derivative is similar to acyclovir -- cellular kinases
If HSV-1 or -2, the triphosphate (DHPGTP) competes with GTP for incorporation into viral DNA. Is incorporated into 'internal' and 'terminal' sites of viral DNA thus inhibiting DNA synthesis.
If CMV-infected cell, ganciclovir-TP levels 10x higher than uninfected cells. Increased levels may persist long after stop giving drug. MOA is competitive inhibition of viral DNA polymerase and direct incorporation of triphosphate into viral DNA stopping chain elongation.
Strong clinical interest because of great potency [sic] and broad spectrum of activity against herpesviruses, especially CMV.
Toxicity: because has 3' hydroxy group on ribose ring can be incorporated into both viral and host DNA. Predict toxicity to rapidly dividing tissues, e.g., bone marrow and GI mucosa as well as gonads. Gonadal toxicity occurs at all doses tested!
FDA approved for CMV retinitis in immunocompromised patients. Reactivation of retinal infection is common when stop drug. To reduce systemic toxicity (once have had the problem), may be recommended to switch to giving drug by intravitreal injection.\dp\pn\pv<0.000>
AMADE90,5:7-5:8
Triazole nucleoside
Effective against both DNA and RNA viruses
Converted to mono-, di-, and triphosphate nucleotides
Phosphorylated derivatives inhibit viral nucleic acid synthesis
Resistance develops slowly
Teratogenic in experimental animals
Generally low toxicity
First generation antiviral acceptable for parenteral Rx in life-threatening diseases.
Purine nucleoside analog
Relatively selective at low to moderate doses. High doses cytotoxic to host cells
Phosphorylated in cell to nucleotide ara-ATP which inhibits DNA polymerase of DNA viruses approx 40 time more than those of host.
Incorporated into DNA virus and host where it terminates elongation.
Primarily used against Herpes virus infections of eye, skin, and CNS (not as good as acyclovir)
Tolerated better in topical treatment of herpes simplex conjunctivitis than idoxuridine and just as effective
Major disadvantage is poor solubility. Requires large volume, slow IV infusions.
Highly toxic so used only in severe cases
Toxicities include gastrointestinal disturbances, CNS symptoms, and bone marrow depression
May be carcinogenic and teratogenic
Rapidly deaminated by adenosine deaminase to hypoxanthine arabinoside. SEARCH for compound resistant to deaminase led to CYLCLARADINE, a carbocyclic analog, which is in clinical trials. (ca. 1990)
Largely replaced by acyclovir for Herpes simplex and varicella-zoster infections.
AMADE90
Idoxuridine is first generation antiviral NOT ACCEPTABLE FOR PARENTERAL USE!
Thymidine analogues
Phosphorylated by thymidine kinases to active triphosphates which inhibit DNA synthesis of virus and host.
Clinical use is topical, too TOXIC when given systemically because produces bone marrow suppression.
Herpes simplex keratitis. Trifluridine may be superior.
AMADE90,p5:5
Investigational drug
Potent inhibitor of HSV-1 and VZV. \IIn vitro\i, is somewhat more potent than acyclovir vs HSV-1; 1000 x more potent vs VZV; 1/50 as potent as acyclovir vs HSV-2.
Selectivity similar to acyclovir; BVDU phosphorylated by herpesvirus thymidine kinase to mono-phosphate.
If HSV-1 (but not HSV-2) infected cell, monophosphate converted to 5'-di- and 5'-triphosphates. Triphosphate inhibits viral DNA polymerase much more than host polymerase. Also incorp into viral DNA more than host. Difference between HSV-1 and -2? HSV-1 induces dTMP kinase which converts mono to diphosphate. The triphosphate inhibits DNA polymerase of both HSV-1 and HSV-2 ... so difference is in activation.
AMADE94, 5:9-5:10
Investigational drug
Potent, selective inhibitor of herpesviruses
Related compounds include fluoromethylarauracil (FMAU) and
MOA and specificity like acyclovir and BVDU
FIAC phosphorylated by herpesvirus thymidine kinase 1,200 to 9,000 times faster than by host T. kinase. FIAC rapidly converted to triphosphate in infected cells where is incorporated into viral DNA by viral DNA polymerase much more than by host DNA polymerase into host DNA. Incorporation into DNA results in 'short chains.'
In vitro, FIAC > acyclovir vs HSV-1. Also active vs HSV-2, and CMV.
CMV has no viral thymidine kinase, but induces host kinase. \In vitro\i therapeutic index is 500 vs. CMV (compared to uninfected cells.)!
Most important drug for palliation of AIDS
Active against HIV-1 and other mammalian retroviruses
Also activity against many Enterobacteriaceae and Giardia lamblia
Decreases reverse transcriptase activity in cultured cells at 0.013 ug/ml.
Inhibits replication of HIV-1 virus in exogenously infected cells at 0.02 to 1.3 ug/ml, but much higher concentrations are required to inhibit replication in chronically infected cells
Also some activity against human lymphotrophic virus type 1 (HTLV-1)
Phosphorylated to triphosphate by cellular enzymes. The triphosphate inhibits viral RNA-directed DNA polymerase (transcriptase) to which it binds more tightly than to human DNA polymerase
Also causes DNA chain termination when azidothymidine triphosphate (phosphorylated zidovudine) is incorporated into DNA. Because 3' position is modified, additional nucleotides cannot be added.
Antiviral activity enhanced by -- acyclovir, interferon, dideoxyadenosine, granulocyte-macrophage colony stimulating factor, neutralizing antibody
Antiviral activity decreased by thymidine and ribivarin, perhaps through competition for phosphorylation, thus decreasing intracellular zidovudine triphosphate (azidothymidine triphosphate) pool.
Resistant strains have been isolated from AIDs patients treatedfor 6 months or more
Resistant strains are still sensitive to dideoxycytidine and foscarnet
PO bioavailability 60 to 65% (no parenteral forms)
Peak concentration after PO administration is 30 to 90 minutes.
Usual dosage is 200 mg q4h!! continuously!!
Adverse effects
Granulocytopenia and anemia in up to 45% of patients. There are a number of risk factors that increase the probability.
Probenecid slows elimination of zidovudine
Efficacious in patients with AIDS and AIDS-related complex
Quality of life is improved over short term.
Overall life expectancy may not be increased according to recent studies, although GG8th90 says estimates at that time were that 1 year survival was 90% versus 50% with no treatment.
Delays appearance of clinical signs of AIDS in HIV seropositive patients.asymptomatic at time treatment is begun.
MOA similar to zidovudine
Promising in phase II and phase III clinical trials for inhibition of HIV replication
Interferons are proteins released by virally infected cells which act on neighboring cells to render them less susceptible to a wide variety of DNA and RNA viruses
Interferons are relatively specific for a species
MOA may differ with interferon
Mode of action depends on virus and cell-type. They bind to specific cell-surface receptors and inhibit viral penetration or uncoating, synthesis or methylation of mRNA, translation of viral proteins, or viral assembly and release. Most prominent effect is to inhibit viral protein synthesis, but in some viruses, there is no inhibition of viral RNA or protein synthesis. (GG8th90)
Following binding to cell surface, interferons may induce synthesis of new cellular RNAs and proteins which mediate the antiviral effect. Antiviral state is not complete until virus invades cell with these new proteins. Three of these proteins are:
Interferons --
The three classes of interferons listed below are synergistic:
Bovine alpha and gamma interferons have been characterized
Interferons can prevent, but not cure viral disease
Alpha-IFN administered IM or IV to humans causes influenza-like signs including fever, headache, malaise, and myalgia. In fact, release of endogenous IFN may be the cause of these signs in viral diseases. Bone marrow suppression is common (thrombocytopenia and granulocytopenia) and Neurotoxicity may also be seen. Other signs of adverse effects also occur.
Interferon alfa-2a [ROFERON-A] and Interferon alfa-2b [Intron A] are given by injection in humans.\dp\pn\pv<0.000>
In humans, interferon alfa is approved for hairy-cell leukemia, AIDS-related Kaposi's sarcoma, and genital warts.
Interferon inducers, agents that stimulate production of endogenous interferons, originally received great attention, but have generally not been found to be safe and effective. These agents included certain microorganisms (e.g., viruses, Rickettsia, Mycoplasma, coliform bacteria), microbial extracts, certain dyes (e.g., methylene blue, acridince orange), tilorone, and synthetic polymers.
AMADE90,5:3-5:4
Combination of inosine and dimepranol acedoben
Efficacy not proven
AMADE90,5:11
Being evaluted against rhinoviruses (common cold).
Proposed MOA is inhibition of macromolecular synthesis by inhibiting viral RNA polymerase, perhaps at a late stage.
Equivocal efficacy vs exptl rhinovirus infections when given via intranasal route.
Intranasal route well tolerated.
Oral drug not well tolerated --> nausea, vomiting, diarrhea, abdominal pain, and headache.
AMADE90,5:11
Pyrophosphate analogue of phosphonoacetic acid (PAA)
In vivo and in vitro activity vs herpes viruses.
May inhibit replication.
AMADE90,5:11
ADME90,5:12,
Acemannan [Carrisyn] -- Binds viral thymidine; immunomodulator
AL-721 -- Alteration of viral envelope or host cell membrane
Amphotericin B methyl ester -- irreversible binding to sterols
Ampligen (mismatched RNA) -- interferon inducer
Castanospermine -- inhibits glycosylation
Soluble CD4 (rST4) -- inhibits viral attachment
Dextran sulfate (UA001) -- inhibits viral adsorption
Dideoxycytidine (ddC) -- reverse transcriptase inhibitor; DNA chain termination
Dideoxyinosine (ddi) -- reverse transcriptase inhibitor; DNA chain termination
Dihydrodideoxythymidine (D4T) -- inhibits viral DNA chain elongation
Foscarnet sodium (PFA, trisodium phosphonoformate) -- reverse transcriptase inhibitor
Fusidic acid -- unknown; possible protease inhibitor
HPA-23 -- reverse transcriptase inhibitor
Interferons (alpha, beta, gamma) -- antiviral; antiproliferative; immunomodulators
Isoprinosine -- antiviral action unknown; immunomodulator
Penicillamine -- Metal chelating agent; cross-links disulfide groups; inactivates viral proteins
Peptide T (octapentide sequence) -- inhibits viral binding to receptor
Ribavirin [Virazole] -- probably interference with viral mRNA synthesis
Rifabutin (ansamycin) -- reverse transcriptase inhibitor
Zidovudine (azidothymidine, AZT) [Retrovir] -- reverse transcriptase inhibitor, DNA chain termination
GG8th90 Douglas, R.G., Jr, Antiviral Agents, Chapter 51, in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 8th ed, eds. A.G. Gilman, T.W. Rall, A.S. Nies, P. Taylor, Pergamon Press, 1990.
Prescott & Baggot, 1988 Antimicrobial Therapy in Veterinary Medicine, Blackwell Scientific Publications, Boston.
Brander91: Brander, G.C., D.M. Pugh, R.J. Bywater, & W.L. Jenkins. 1991. Chapter 35, Antifungal and Antiviral agents. in Veterinary Applied Pharmacology & Therapeutics, 5th ed. . Bailliere Tindall, London.
AMADEnn American Medical Association Drug Evaluations Subscription, 1990 to present. Date reflects date on page used in citation, e.g., AMADE90 indicates 1990.