Year : 1997 | Volume
: 45 | Issue : 4 | Page : 203--210
Ophthalmic antiviral chemotherapy : An overview
S Athmanathan, P Garg, GN Rao
Devchand Nagardas Jhaveri Microbiology Centre, L.V. Prasad Eye Institute, Hyderabad, India
Devchand Nagardas Jhaveri Microbiology Centre, L.V. Prasad Eye Institute, Hyderabad
Antiviral drug development has been slow due to many factors. One such factor is the difficulty to block the viral replication in the cell without adversely affecting the host cell metabolic activity. Most of the antiviral compounds are analogs of purines and pyramidines. Currently available antiviral drugs mainly inhibit viral nucleic acid synthesis, hence act only on actively replicating viruses. This article presents an overview of some of the commonly used antiviral agents in clinical ophthalmology.
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Athmanathan S, Garg P, Rao G N. Ophthalmic antiviral chemotherapy : An overview.Indian J Ophthalmol 1997;45:203-210
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Athmanathan S, Garg P, Rao G N. Ophthalmic antiviral chemotherapy : An overview. Indian J Ophthalmol [serial online] 1997 [cited 2023 Jun 10 ];45:203-210
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Development of antiviral drugs have lagged behind due to many problems unlike the rapid development of antibacterial antibiotics. Much of it can be attributed to the virus itself. It is difficult to block the viral activity in the cell without adversely affecting the host cell metabolic activity since viruses replicate using host cell machinery. Most of the antivirals available today, mainly inhibit viral nucleic acid synthesis without unduly harming the host cells, while leaving the host cell unaffected. There are few drugs which inhibit viral entry into the cell or block viral protein synthesis. Other problems include the nature of viral illness and latency of viruses. Unlike bacterial infection, by the time symptoms and signs appear, the viral infection has spread and the viraemia has already occurred. Diagnosis is difficult during incubation period and laboratory diagnosis of viral infections are often delayed. Antivirals have failed to act on viruses which undergo latency like herpes simplex virus (HSV) and varicella zoster virus (VZV), since these drugs act only on actively replicating viruses.
Viral replication involves a series of events. [Figure:1] shows the various stages of viral replication and the antivirals acting at various sites.
Most of the antiviral drugs available today are analogs of nucleosides. [Figure:2] shows the structures of various antiviral drugs.
IDU is a thymidine analog. This drug is activated by both cellular and viral thymidine kinases to form a triphosphorylated derivative. Phosphorylated drug then competes with the naturally occurring thymidine in deoxyribonucleic acid (DNA) chain elongation, ultimately resulting in the production of a defective DNA resulting in chain termination. Since both cellular and viral enzymes activate the drug, side effects include severe host cell toxicity. It was formerly used systemically but because of associated toxicity and lack of demonstrable efficacy its systemic use has largely been abandoned. Topical IDU is effective in the treatment of HSV keratitis particularly superficial epithelial infections.
IDU has been used in HSV keratitis. Topical application of a 1% solution or 0.5% ointment for ocular use, given for 2 weeks cures 75% of HSV keratitis. Treatment should not be prolonged beyond 3 weeks since this may lead to corneal toxicity. It is used both for primary as well as recurrent HSV keratitis. The drug does not penetrate cornea and is water insoluble, hence has little activity in stromal keratitis.
Toxicity to cornea, conjunctiva, and lids are seen on prolonged use of IDU. It includes blepharitis, papillary conjunctivitis, punctal occlusion, superficial punctate keratopathy, delayed epithelial healing, ghost dendrites and scarring. If no healing is seen within 2 weeks, probably the virus is resistant to IDU and an alternative drug should be used.
Trifluridine is also an analog of thymidine. The mechanism of action is different. It inhibits the enzyme thymidine synthetase thus inhibiting DNA synthesis, both in the virus as well as in the host cell. It also competes with naturally occurring thymidine and gets integrated into DNA chain, thus producing faulty DNA and inhibiting virus replication.
Trifluridine is available as a 1% solution. It can be used both in primary and recurrent HSV epithelial keratitis like idoxuridine. A number of reports suggest that trifluridine is superior to idoxuridine and vidarabine in the treatment of dendritic and geographical HSV keratitis. When there is no improvement in the healing of the ulcer with IDU and vidarabine, treatment with trifluridine has shown the healing to be better in majority of the cases. It has also been shown to be useful in Thygeson's superficial punctate keratitis. All these beneficial effects seen makes trifluridine the drug of choice in the treatment of HSV epithelial keratitis.
Adverse effects of trifluridine are much less when compared to vidarabine or IDU. Prolonged use of trifluridine causes irritation, delayed epithelial healing, conjunctival keratinisation and scarring. Discontinuation of the drug often reverses these adverse effects.
Zidovudine (Azidothymidine, AZT)
Zidovudine is another thymidine analog, and it was the first drug approved for the treatment of patients with acquired immunodeficiency syndrome (AIDS). It inhibits human immunodeficiency virus (HIV) replication in vitro. The cellular enzymes convert the drug into a triphosphate form which inhibits reverse transcriptase. This active form also acts as the substrate for reverse transcriptase. The drug is further incorporated into the elongating DNA, blocking the formation of proviral DNA and chain termination occurs.
Zidovudine has been mainly used in asymptomatic and early stages of HIV disease, when CD4 counts are ≤500/μl. It delays the progression of asymptomatic HIV infection and when administered in later stages of the disease, decreases the mortality and reduces the risk of acquiring opportunistic infections. In ocular infections, the drug has been used to treat cytomegalovirus (CMV) retinitis, HIV induced iridocyclitis and anterior uveitis in patients with AIDS.
Dosage and routes of administration
Zidovudine is given orally and most commonly employed dosage is 200 mg eight hourly. Comparative dosage studies indicate that a total daily dose of 500-600 mg is as effective and less toxic than when higher doses are administered.
Zidovidine may induce bone marrow suppression (anaemia, granulocytopaenia, leucopaenia) and less commonly nausea, vomiting, myalgia, and malaise. Bone marrow suppression may further lead to infections in these patients.
Vidarabine is a adenosine analog. It is converted to vidarabine phosphate by cellular and viral kinases. phosphorylated drug is a potent inhibitor of viral (HSV) DNA polymerase while its action on host cell DNA polymerase is less efficient. Hence at low doses of the drug, a selective inhibition of viral DNA polymerase occurs leaving that of the host cell unaffected, resulting in blocking of viral DNA synthesis.
Vidarabine is available as ophthalmic ointment (3%) and intravenous (IV) preparation. As the drug is poorly soluble it is administered as a constant twelve hours infusion. The dose frequently recommended is 10-15 mg/kg/day.
The ophthalmic ointment of vidarabine is effective in the treatment of HSV keratitis. The treatment is not generally extended beyond three weeks for the fear of toxicity. Vidarabine has been found to be as effective as IDU and is also found to be effective in patients not responding to IDU therapy. However, trifluridine was found to be more effective than vidarabine in geographical ulcers. In the therapy of herpes zoster, vidarabine administered systemically resulted in reduction of rates of cutaneous and visceral dissemination and of post herpetic neuralgia but was less effective overall than acyclovir in a comparative trial. This drug has been found to be effective in the therapy of HSV encephalitis in a placebo controlled trial but comparative studies indicate that acyclovir is more effective even for this indication.
Side effects of vidarabine are similar to those caused by trifluridine and are dose related. They include haematopoietic side effects like anaemia, leukopenia and thrombocytopaenia. Neurotoxicity has been reported particularly when higher doses are administered and in patients with hepatic and renal insufficiency.
Acyclovir is an analog of guanosine (9-[(2-hydroxyethoxy) methyl] guanine). It is a highly potent and selective inhibitor of replication of certain herpes viruses including HSV-1, HSV-2, VZV, and Epstein Barr virus. It is relatively ineffective against human CMV infections.
The high degree of selectivity of acyclovir is related to its unique mechanism of action. Acyclovir is phosphorylated to acyclovir monophosphate. This occurs more efficiently in herpes virus infected cells by means of a virus coded thymidine kinase. In uninfected cells, little phosphorylation occurs and hence the drug is concentrated in virus infected cells. Acyclovir monophosphate is subsequently converted by host cell kinases to a triphosphate form which is a potent inhibitor of virus induced DNA polymerase with relatively little effect on host cell DNA polymerase. Acyclovir triphosphate is also incorporated into the elongating viral DNA resulting in DNA chain termination. Thus normal cellular function (DNA synthesis) is unaffected while in infected cells, the virus replication is inhibited. This highly selective property makes acyclovir a potent antiherpetic drug with virtually no side effects.
Acyclovir is available as intravenous, oral and topically administered forms. Topically it is available as 3% ointment. Topical acyclovir (3% ointment) has been successfully used in epithelial keratitis. Healing rates are comparable with that of 1% IDU ointment. Acyclovir has been proven to be superior to IDU in treating HSV dendritic ulcers, wherein healing has been observed to occur faster. Further, epithelial toxicity is much less often observed with acyclovir compared to IDU. Acyclovir and vidarabine treatment for HSV dendritic and geographical ulcers has been compared and no differences in healing rates or times were observed between the two drugs and patient groups. When compared with trifluridine in treating HSV keratitis, success rates were the same. Acyclovir can also be given orally. A masked controlled trial indicated that oral acyclovir 200 mg five times daily for 2-3 weeks is effective in resolving infectious epithelial keratitis.[19, 20] These results could not be confirmed by another group despite documentation of the presence of viral particles in the corneal stroma of the patients. In an open trial on the effect of long term oral acyclovir on recurrence rates of infectious HSV keratitis, it was found that there was a highly significant drop in the recurrence rate while the patients were on this regimen. The effect of oral acyclovir in ocular herpes is thus not well established and is currently the subject of the ongoing Herpetic Eye Disease Study., In this study oral acyclovir is being used in the treatment of HSV stromal keratitis over a 70 day period.
On the basis of information presently available, following is the list of patients with herpes infections of the eye in whom oral acyclovir with or without topical antiviral therapy may be indicated.
a. Patients with primary HSV keratitis.
b. Patients with infectious epithelial keratitis and a topical disease such as eczema.
c. Immunosuppressed patients such as those with AIDS, organ transplant recipients, and those with blood dyscrasias.
d. Those at risk of recurrence of infectious disease more than twice annually.
e. In patients where keratoplasty has been performed for active HSV keratitis.
f. In herpes zoster, oral acyclovir has been shown to be an excellent drug and reduce significantly the incidence and severity of secondary ocular inflammatory disease., Recommended oral doses are 200-400 mg five times a day. In moderately or severely immunosupressed patients, IV acyclovir is required in place of oral acyclovir because of the adequate serum levels achieved by the IV route. IV dose for acyclovir is 5 mg/kg body weight, eight hourly. It has also been used in acute retinal necrosis syndrome caused by HSV and VZV. Intravitreal acyclovir has also been used in this syndrome the dose being 5 μgm/0.1ml administered weekly.
Overall, acyclovir is remarkably well tolerated and generally free of toxicity. The most frequently encountered toxicity has been renal dysfunction particularly with rapid intravenous administration. Acyclovir is excreted unmetabolized primarily by the kidney, both by glomerular filtration and tubular secretion. Reduction in dosage is indicated in patients with abnormal creatinine clearance. Topical acyclovir is safe and side effects are not frequently encountered.
In AIDS patients, chronic or intermittent administration of acyclovir has been associated with development of resistance and clinical failure. The most common mechanism of resistance is a deficiency of the virus induced thymidine kinase. These patients with resistance to acyclovir frequently respond to foscarnet.
Famciclovir is a prodrug for penciclovir with similar action like acyclovir. It also inhibits viral DNA polymerase. It has good bioavailability when compared to acyclovir, gets absorbed from gastrointestinal tract faster and thus has the advantage of requiring smaller doses. Its use remains to be established.
Ganciclovir (9-[(l, 3-dihydroxy-2-propoxy)methyl] guanine) has activity against all herpes viruses but the difference in the chemical structure makes it 10-25 times more active against CMV. The drug gets activated when it is converted to triphosphate form which inhibits CMV DNA polymerases and can be incorporated into CMV DNA with eventual termination of DNA chain elongation. CMV unlike HSV does not code for its own thymidine kinase and hence ganciclovir is phosphorylated by a virus coded protein kinase and /or cellular kinases.
Ganciclovir is available only for intravenous administration. The most commonly employed dose for initial therapy is 5 mg/kg twice a day for 14-21 days followed by a maintenance dose of 5 mg/kg/day for 5 days/week. There are reports of intravitreal administration of this drug. No retinal toxicity was found.[28-31] Ganciclovir has been utilised extensively in the treatment of CMV infections in AIDS and otherwise immuno-suppressed patients and has been approved by the United States Food and Drug Administration for CMV retinitis. It has also been used to treat other CMV associated syndromes.
Bone marrow toxicity has been reported with ganciclovir particularly when other bone marrow suppresants such as zidovudine are used concomitantly. Hence, its use should be withdrawn when zidovudine therapy has been started. Intravitreal ganciclovir administration has not been shown to cause any retinal toxicity when administered in usual doses.
Didanosine is an guanosine analog resembling zidovudine in structure. Triphosphate form of the drug inhibits reverse transcriptase and also can act as chain terminator during DNA chain elongation.
Didanosine has been approved for use in AIDS patients who are either unresponsive to zidovudine or cannot tolerate the drug. This drug has been found to be active against most HIV isolates resistant to zidovudine.
Didanosine is given orally. It is highly acid labile, and so it must be administered with buffers acting against stomach acidity. The plasma half life is 1.5 hours and approximately 50% of the dose is cleared by the renal system. However, the intracellular half life of active drug is considerably longer (8-24 hours) and provides the rationale for the recommended dosing schedule of every 12 hours.
These include painful peripheral neuropathy, acute pancreatitis and retinal pigment epithelial lesions. Didanosine is not as toxic as zidovudine to bone marrow, so it can be concurrently used with ganciclovir and may be particularly helpful in the setting where haematopoietic suppression is present or anticipated.
Zalcitabine is an cytidine analog. Its triphosphate form inhibits HIV replication by inhibiting viral reverse transcriptase and induces DNA chain termination.
Zalcitabine has been administered along with zidovudine to AIDS patients showing marked clinical or immunological deterioration.
A painful peripheral neuropathy and pancreatitis may be encountered with zolcitabine.
Foscarnet (phosphonoformic acid) is a pyrophosphate containing compound which is a potent inhibitor of herpes viruses including CMV. It inhibits viral DNA polymerases at the pyrophosphate binding site, at concentrations which have relatively little effect on cellular polymerases. Because foscarnet does not require phosphorylation to exert its antiviral activity it is active against acyclovir resistant herpes virus and gancyclovir resistant CMV. Foscarnet also inhibits reverse transcriptase of HIV and is active against HIV in vivo.
Foscarnet has been licensed for the treatment of CMV retinitis in patients with AIDS. In a comparative clinical trial, it appeared to have efficacy similar to that of ganciclovir. It has also been used to treat acyclovir resistant HSV and VZV infections and ganciclovir resistant CMV infections. It has also been tried intravitreally in the treatment of CMV retinitis., 
Foscarnet is poorly soluble and must be administered intravenously in a dilute solution infused over 1-2 hours. The drug is primarily eliminated by kidneys. Most common initial dosage is 60 mg/kg every 8 hours for 14-21 days followed by a maintenance dose of 90-120 mg/kg once daily.
The major toxicity of foscarnet is renal impairment. Renal function should be monitored closely particularly during initial phase of therapy. Since the drug binds divalent metal ions hypocalcaemia, hypomagnesaemia, hypokalaemia and hypophosphataemia may ensue. Foscarnet is not a immuno-suppressive and may be administered concomitantly with zidovudine.
Cidofovir is (S)-l-(3-hydroxy-2-phosphonyl methoxypropyl) cytosine, a broad spectrum and long acting nucleoside monophosphate analog of cytosine, that appears to act by inhibiting viral DNA polymerase. This drug is active against many viruses including HSV 1 and 2, CMV, VZV and adenoviruses. Most of its activity has been proved in animal experiments. It seems to be a promising drug for the treatment of adenoviral ocular infections.
From the earliest descriptions, considerable interest has existed in the application of interferon for the prophylaxis and/or therapy of viral infections. Interferons are cytokines with broad antiviral activities [Figure:3] as well as immunomodulating and antiproliferative actions.
DNA recombinant technology has made available highly purified alpha, beta, and gama interferons. Interferon is licensed in the United States for the treatment of chronic hepatitis B (alpha and beta), chronic non-A non-B hepatitis and hepatitis C virus infection, condyloma acuminatum, hairy cell leukaemia and Kaposi's sarcoma. The most common dose regimen is 1-3 million units three times per week for 16-24 weeks. Intralesional injections can also be administered to cure warts.
Adverse effects include fever chills, myalgia and fatigue. Approximately 25% of patients require dose reduction but fewer than 5% will require discontinuation of therapy.
An ideal antiviral drug would be one that acts only on viruses without causing any deliterious effect on host cells, possess antiviral activity against a wide range of viruses, is cost-effective and easily available. To date, no antiviral agent meets such requirements. Newer technologies employed in drug discovery may yield such an ideal antiviral agent in the future.
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