antiviral drugs against herpes infections - medIND

Indian Journal of Pharmacology 2000; 32: 330-338

EDUCATIONAL FORUM HERPES INFECTION AND ANTI VIRAL AGENTS

ANTIVIRAL DRUGS AGAINST HERPES INFECTIONS MADHU VAJPAYEE1, NEENA MALHOTRA2 1Department

of Microbiology, 2Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi-110 029.

Manuscript Received: 1.11.99

Revised: 12.1.2000

Accepted: 27.4.2000

SUMMARY

Several new and promising antiviral drugs have been approved which allow better options to control infections caused by herpes virus. Vidarabine has been the earliest available drug against herpes simplex (HSV) and varicella zoster (VZV), but is an agent that is rarely used at present. Acyclovir has replaced vidarabine in treating herpes infections in immunocompetent and immuno compromised patients. The low oral bioavailability of acyclovir, as well as emergence of drug resistant strains have stimulated efforts towards development of newer compounds for treatment of herpes infection. These include penciclovir and its oral prodrug famciclovir and the oral prodrug form of acyclovir, valacyclovir. These drugs are dependent on virus encoded thymidine kinase (TK) for their intracellular activation (phosphorylation) and, upon conversion to their triphosphate form which act as inhibitors/alternative substrate of viral DNA polymerase. Therefore resistance of these drugs may occur for virus mutants that are TK-deificient. Newer drugs as Sorivudine which is a nucleoside analogue has been pursued in treating herpes infections. Foscarnet, which does not require any previous metabolism to interact with viral DNA polymerase is useful in clinical settings when TK deficient mutant strains emerge. Cidofovir, an acyclic nucleoside phosphonate is yet another available drug to which TK deficient strains are sensitive. This review describes these currently available antiviral drugs against herpes virus, some approved and others under clinical evaluation for approval.

KEY WORDS

Herpes infection antiviral agents herpes simplex varicella zoster penciclovir famciclovir acyclovir valacyclovir vidarabine

INTRODUCTION Herpes virus (herpes simplex, varicella zoster, cytomegalovirus) are the causative agents of a wide variety of infections in human. While lesion in immunocompetent patients may be benign, those in immunocompromised patients can be life threatening with high mortality and morbidity. The development of successful antiviral agents against these infections had been slow until the last decade. However progress in organ transplant, cancer therapy and the upsurge of human immuno deficiency virus (HIV) have stimulated efforts towards the development of newer compounds for the treatment of individuals with herpes infection. The currently available antiviral drugs have been targeted at following molecular sites of herpes virus. I. Thymidine kinase (TK) phosphorylation, targeted at DNA polymerase - these are nucleoside analogue Correspondence: M.Vajpayee e-mail: [email protected]

sorivudine

cidofovir

requiring phosphorylation by viral TK and include acyclovir and its prodrug valacyclovir, ganciclovir, penciclovir and its prodrug famciclovir, sorivudine and brivudine. II. Drugs not dependent on viral TK phosphorylation, targeted at viral DNA polymerase viz vidarabine, foscarnet and cidofovir. The pharmacokinetics, dosage and drug interactions of the approved drugs are given in Tables 1, 2 and 3 respectively. Acyclovir: Acyclovir {9-[(2-hydroxyethoxy) methyl] guanine, zovirax} is a guanosine analogue with an acyclic side chain at the 9 position. It is a prototype of the group of viral agents that are activated by viral thymidine kinases (Tk) to become inhibitors of viral DNA polymerases and block viral DNA synthesis. Acyclovir uptake and intracellular phosphorylation to monophosphate is mediated by viral thymidine

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MADHU VAJPAYEE AND NEENA MALHOTRA

Table 1. Antiherpes viral agents - Pharmacokinetic properties. Agent

Oral bioavailability

Half-life (hours)

Major route of elimination

Acyclovir

15-30%

3

Mainly renally excreted unchanged

Valacyclovir

55% (of acyclovir)

3

Renal

Ganciclovir

5%

3-4


Famciclovir

77%

3

Penciclovir catabolite is renally excreted

Foscarnet

N/A

4.5-8.2

Renal

Sorivudine

60%

6


Cidofovir

N/A

2.6

Renal

Vidarabine

N/A

3.5

Metabolized to arabinoxyl byoxanthine

Trifluridine

N/A

N/A

Negligible systemic absorption and metabolism

Idoxuridine

N/A

N/A

Negligible systemic absorption and metabolism

kinase. It is further converted to triphosphate by cellular enzymes, which competitively inhibits viral DNA polymerases. The triphosphate is incorporated into elongated DNA chains as monophosphate where it acts as chain terminator because of lack of 3' hydroxyl group. Inactivation of viral DNA polymerase occur following formation of complex between terminated DNA template and the enzyme.

Clinical pharmacology and toxicity: Acyclovir is available in topical, oral and parenteral preparations. The drug is widely distributed and CSF levels are approximately half of plasma levels. The drug is mainly excreted by kidney. HSV 1 and 2 are more sensitive to the inhibitory effects of acyclovir than is VZV. The inhibitory doses range from 0.1 to 0.6 µM for HSV, whereas for VZV they are 3-4 µM. It is a remarkable nontoxic drug. The major toxicity of parenteral acyclovir has been renal dysfunction1. Clinical status: Acyclovir has been extensively studied in both immunocompetent and immunocompromised hosts for both prophylaxis and treatment of herpes virus infection. The intravenous formulation is used for treatment of herpes simplex encephalitis in nor mal hosts and VZV infections in immunosuppressed subjects and is shown to be superior to vidarabine in this respect. The same formulation is used for treatment of neonatal HSV infection2,3. Parenteral acyclovir is the agent of choice for serious mucocutaneous, visceral or central nervous system disease due to HSV or VZV, unless resistance is suspected. The lower susceptibility of VZV

isolates is taken care by higher dose of acyclovir. Acyclovir decreases the period of virus shedding and speeds healing in patients with primary genital HSV infection4. Topical acyclovir demonstrates some efficacy for primary genital HSV infection, but is ineffective in recurrent infection5. Oral acyclovir is very effective for the suppression of recurrent genital herpes in normal host. It reduces recurrence by approximately 90% 6. Oral acyclovir is beneficial for treatment of herpes. It is known to reduce the pain consistently. Acyclovir has been shown to be effective in prophylaxis of HSV infections in immunosuppressed patients7 as in organ or bone marrow transplantation cases and cancer patients receiving chemotherapy. It is also effective in prophylaxis of CMV infection in renal, liver and bone marrow transplant recipients.

Resistance: Resistance of HSV to acylovir develops readily in vitro and also in vivo 8. Three basic mechanism have been identified-altered Tk substrate specificity, absent or partial production of viral Tk and altered viral DNA polymerase. The most common mechanism found in clinical isolates is deficient TK activity. Acyclovir resistant isolates of HSV have been observed in immunocompromised individuals, especially AIDS patient9. Acyclovir resistance in AIDS patients usually includes progressive cutaneous disease with chronic ulcerative mucocutaneous lesions, prolonged viral shededing, poor healing and local spread, despite acyclovir therapy. Acyclovir resistant VZV isolates have also been obtained from immunocompromised patients.

HERPES INFECTION AND ANTI VIRAL AGENTS Table 2. Antiherpes viral agent - Drug interaction characteristics. Agent

Indication

Dosing

Toxicity

Acyclovir

Immunocompetent host

500m P.O. tds X 7-10 days or 5mg/kg i.v. q8h initially in more severe cases ( e.g. accompanied by aseptic meningitis 500mg P.O. tds X 5 days 400mg P.O. tds 10 mg/kg i.v. q8h X 14 days

Headache, nausea, neurotoxicity, nephrotoxicity

Genital HSV infection Primary, Recurrent, Suppression, Herpes simplex encephalitis or other invasive syndromes, VZV infection.

Immunosuppressed host Mucocutaneous HSV infection Primary, Recurrent, Suppression, Invassive HSV infection, VZV infection. CMV prophylaxis in transplant recipients.

800mg P.O. 5id X 7 days or 10mg/kg i.v. q8h X 7 days if invasive (e.g. encephalomyelitis)

400mg P.O. 5id X 7-10 days or 5mg/kg i.v. q8h in more severe cases 400mg P.O. 5id X 7-10 days 400mg P.O. bid-tid 10mg/kg i.v. q8h X 14 days 800mg P.O. 5id X 7 days or 10mg/kg i.v. q8h X 7 days if invasive (e.g. encephalomyelitis) 800mg P.O. quid - 5id

Valacyclovir

Recurrent genital HSV, Herpes zoster in immunocompetent hosts.

500mg P.O. qid X 5 days 1g P.O. tds X 7 days

Ganciclovir

HIV-infected host CMV retinitis

5 mg/kg i.v. q12h X 14-21 Neutropenia, thrombocytopenia days induction treatment followed by maintenance therapy (5-6 mg/kg i.v. qd or 1g P.O. tid or ocular implant 5mg/kg i.v. q12h X 14-21 days (need for maintenance not proven but advisable)

CMV gastrointestinal or central nervous system disease, Other immunosuppressed host: CMV hepatitis, gastrointestinal or central nervous system disease, CMV pneumonia in bone marrow transplant recipients.

5mg/kg i.v. q12h X 14-21 (maintenance therapy not generally necessary) 5/kg i.v. q12h X 14-21 combined with intravenous immuno(for CMV hyperimmune) globumin

Prophylaxis or pre-emptive therapy of CMV.

2.5mg/kg i.v. qd to 5mg/kg i.v. q12h during “risk” period (Optimum dose and duration not yet identified. (Oral formation under investigation for CMV prophylaxis in non-HIV infected Immune suppressed hosts).

HIV- or non-HIV-infected immunosuppressed host, Invasive-HHV-6 disease.

5mg/kg i.v. q12h X 14-21 days

Same as acyclovir, association with HUS/TTP

332

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Famciclovir

Herpes zoster in immunocompetent hosts, Recurrent genital HSV,

500mg P.O. tid X 7 days 125mg P.O. tid X 5 days

Headache, nausea,hemorrhagic pancreatitis (single report)

Foscarnet

HIV-infected host CMV retinitis

60mg/kg i.v. q8h or 90 mg/kg i.v. q12h X 14-21 days for induction treatment followed by maintenance therapy (90-120mg/kg i.v. qd)

Nephrotoxicity, electrolyte disturbances, neurotoxicity, anemia, neutropenia

CMV gastrointestinal or CNS disease

60mg/kg i.v. q8h or 90mg/kg i.v. q12h X 14-21 days (need for maintenance therapy not proven but advisable)

Other immunosuppressed host CMV disease

60mg/kg i.v. 18h or 90mg/kg i.v. q12h X 14-21 days

HIV- or non-HIV-infected immunosuppressed host

40mg/kg i.v. q8h or 60 mg/kg i.v. q12h X 14 days

Acyclovir-resistant HSV or VZV 60mg/kg i.v. q8h or 90mg/kg i.v. infection q12h X 14-21 days Invasive HHV-6 disease Sorivudine

Herpes zoster in immunosuppressed hosts

40mg P.O. qd X 7 days (still investigational)

Headache, nausea, vomiting, hepatic enzyme elevation

Cidofovir

CMV retinitis

5mg/kg i.v. qw X 2 weeks, then 5mg/kg i.v. every other week (combined with probenecid for nephroprotection)

Nephrotoxicity, cardiomyopathy rash, iritis, rashiritis (with intravitreal administration)

Vidarabine

Herpes simplex keratitis, Systemic use supplanted by other, more effective and less toxic agents

Apply to conjunctiva 5id 15mg/kg i.v. qd

Nausea, vomiting, diarrhoea, leukopenia, thrombocytopenia, neurotoxicity

Trifluridine

Herpes simplex keratitis

1 drop of 1% solution q2h (maximum 9 drops/day) X 10 days

Local eye irritation mutagenic, carcinogenic, and teratogenic potential

Idoxuridine

Herpes simplex keratitis

1 drop q2h Local eye irritation, mutagenic, carcinogenic, and teratogenic potential. DMSO preparation can be associated with headache, light headedness and nausea

HERPES INFECTION AND ANTI VIRAL AGENTS

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Table 3. Indications, dosing regimens and toxicity of antiherpes viral drugs. Agent

Drug interactions

Acyclovir

?Additive effects with other neuro or nephrotoxic agents (e.g. cyclosporine)

Valacyclovir

Same as acyclovir; cimetidine and probenecid decrease rate but not degree of valacyclovir to acyclovir conversion

Ganciclovir

Bone marrow suppressive agents: increased risk of myelosuppression. Imipenem; increased risk of seizures

Famciclovir

Probenecid, theophylline, increase famciclovir plasma levels. Digoxin levels increased

Foscarnet

Nephrotoxic agents: increased risk of foscarnet nephrotoxic adverse effects. Pentamidine: increased risk of hypocalcemia. Ciprofloxacin:increased risk of seizures

Sorivudine

Fluorinated pyrimidines: (e.g. 5-fluorouracil) increased risk of myelosuppression

Cidofovir

Probenecid: nephroprotective at cidofovir doses of >3mg/kg

Vidarabine

Allopurinol and interferon : increased risk of neurotoxicity

Trifluridine

None reported

Idoxuridine

None reported

Valacyclovir: Valacyclovir [2-(2 amino-1,6-dihydro6-oxo-9H purine 9yl-methothy) ethyl L-valinate hydrochloride, Valtrex] is the L-valylester of acyclovir. It was designed to enhance oral bioavailability of the parent compound. It is an oral preparation that is rapidly absorbed from the gastrointestinal tract. The spectrum of activity is identical to that of acyclovir. The drug interaction and side effects are identical to that of the parent drug. It is demonstrated to be effective in treatment of herpes zoster infection in normal individuals10. Valacyclovir is shown to be beneficial in treatment of recurrent genital HSV infection10. Ganciclovir: Ganciclovir [9-(1,3 dihydroxy-2propoxymethyl ) guanine] is an acyclic analogue of guanosine that differs from acyclovir in having an additional hydroxymethyl group on the acyclic side chain. Viral DNA is inhibited by ganciclovir11. Intracellular ganciclovir is phosphorylated to the phosphate derivative by virus encoded TK during HSV and VZV infection and by a viral protein kinase encoded by the UL97 gene during CMV infection12. Cellular enzymes further convert it to diphosphate and triphosphate form. Ganciclovir triphosphate is a competitive inhibitor of deoxy guanosine triphosphate (dGPT) incorporation into DNA and preferentially inhibits viral rather than host cellular DNA polymerase. Incorporation of ganciclovir triphosphate into viral DNA causes a slowing and subsequent cessation of viral DNA chain elongation. Ganciclovir has greater anti CMV activity than its inhibitor activity against other herpes viruses12.

Clinical pharmacology and pharmacology: Current ganciclovir formulations have very limited bioavailability (13%), although high dose (1000 mg 3 times daily) oral ganciclovir may be adequate for maintainence therapy after IV induction. Following intravenous doses of 7.5 mg/kg, peak serum levels of ganciclovir range between 18 and 24 µM with CSF levels from 2 to 3 µMs; The half life of ganciclovir is 3-4 h. Renal excretion is the major route of elimination, and doses must be reduced during renal impairment. Ganciclovir has a narrow therapeutic toxic ratio and causes reversible neutropenia or thrombocytopenia which often requires granulocyte-colony stimulating factor (G-CSF) support. Clinical status: Ganciclovir is useful for the treatment and prophylaxis of CMV infections in immunocompromised host. It is especially beneficial in treatment of CMV in HIV patients11. Induction course must be followed by maintainance therapy otherwise recurrence and progression of CMV retinitis will occur. Ganciclovir is delivered locally by ocular implant in patients intolerant to systemic ganciclovir. It is also effective for gastrointestinal disease due to CMV in HIV patient14. Combination therapy with foscarnet has shown that these two agents can be used safely when administered concurrently or in alternating regimen. Ganciclovir appears effective for invasive CMV disease in solid organ transplant recipient but its response is variable in bone marrow transplant recipients. Effective regimens have included initiation at the time of

335


333transplantation, post-transplantation when CMV is isolated and as pre-emptive short term regimen15.

Resistance: Resistance in CMV isolates occurs by two mechanisms, viral DNA chain elongation is slowed down and subsequently ceased by incorporation of ganciclovir triphosphate into viral DNA. There is reduced intracellular ganciclovir phosphorylation due to alternation in viral enzyme encoded by UL97 gene16,17. Point mutations in viral polymerase leads to partial resistance to ganciclovir. Ganciclovir resistance has been recognized clinically by progressive disease and persistant CMV recovery, despite therapy18. Foscarnet therapy may benefit patients with ganciclovir resistant CMV infection. Famciclovir and penciclovir: Famciclovir {[9-(4 hydroxy-3-hydroxymethylbut l-yl) guanine Famvir]} is the inactive diacetyl 6-deoxy prodrug ester of penciclovir [9-(4 hydroxy-3-hydroxy-3-hydroxymethylbut 1-yl) gaunine], an acyclic nucleoside analog of guanosine. Penciclovir has similar mechanism of action except that it is not an obligate chain terminator. Famciclovir has a bioavailability of 77% and is rapidly converted to its active form, penciclovir by deacetylation and oxidation. It is generally well tolerated. Headache and nausea are predominant complaints with the drug. Famciclovir is approved in the United States for the treatment of herpes zoster and recurrent genital HSV infection in immunocompetent host. Foscarnet (phosphonoformate): Foscar net (trisodium phosphonoformate, Foscavir) is a nonnucleoside derivative with antiviral activity against herpes viruses. Foscarnet is a pyrophosphate analogue that is a noncompetitive inhibitor of the viral polymerase. It does not require intracellular activation but evidently inhibits DNA polymerase directly by interacting with the pyrophosphate binding site to block binding of the pyrophosphate moiety that is cleared from a dNTP during DNA synthesis19.

Clinical pharmacology and toxicity: The drug is not orally bioavailable and intravenous administration is required because of its highly alkaline pH. Foscarnet is cleared rapidly from the blood after intravenous administration but is not metabolized. About 10-30% of the dose accumulates in bone, the remainder being excreted unchanged in urine. Nephrotoxicity is the most common adverse event. Adjustment of

foscarnet dosage for decrease in kidney function and adequate maintainance of intravascular volume are required during therapy to minimize nephrotoxicity. Seizures and anemia are known toxicity which can also be drug related. Neuropathy and penile ulcers have also been described with foscarnet.

Clinical status: Foscarnet is effective in treatment for CMV retintis, either as primary therapy or when there is ganciclovir resistance. In a multicentre trial of foscarnet versus ganciclovir, the two drugs were equivalent with respect to CMV outcome, but the foscarnet group showed an improved survival, extending life by an average of 4 months19. Foscarnet is useful for ganciclovir resistant CMV retinitis and acyclovir resistant mucocutaneous HSV or VZV infection, in patients with HIV infection20,24,25. Foscarnet can be used with ganciclovir in management of CMV in patients with AIDS 21. It may have a role in prophylaxis against CMV infection in marrow transplant recipients. Resistance: Foscarnet is specific inhibitor of HSV and CMV polymerase22. The mechanism of resistance to foscarnet involves alteration in binding to the polymerase. Acyclovir or cidofovir (HPMPC)23,24 can be used for foscarnet resistant HSV infections. β -D-arbinofuranosyl E-5 Sorivudine: Sorivudine (1-β [ 2-bromovinyluracil] Bravavir) is an experimental nucleoside analogue that has been developed exclusively for the treatment of VZV infection26. The drug has activity against HSV-1 and EBV but not HSV-2 or CMV. Sorivudine triphosphate is a competitive inhibitor of viral DNA polymerase but does not act as DNA chain terminator. Cellular enzymes completes the intracellular metabolism to triphosphate form.

Clinical pharmacology and toxicity: The plasma half life is 6 hours, the major route of excretion is renal with up to 75% of an administered dose excreted unchanged in urine. The dosing schedule of the drug is on a once daily basis26. It is generally well tolerated with headache and gastrointestinal symptoms being the most common adverse effect. Clinical status: Sorivudine is being developed for treatment of VZV infection. It has advantage of potency and the convenience of once daily regimen over currently available antiherpes drug. Resistance: VZV isolates with mutations in the thymidine kinase gene leading to enzyme deficiency or

HERPES INFECTION AND ANTI VIRAL AGENTS

alternation are resistant to sorivudine. Brivudine is similar to sorivudine in mechanism of action and has been successfully used for VZV infection. Currently it is being used as once daily dosage for treating herpes zoster. Cidofovir: Cidofovir {(S)-1-[3-hydroxy-2 (phosphonylmethoxy)-Propyl] cytosine, HPMPC, Vistide} is an acyclic phosphonate nucleoside analogue that belongs to a family of phosphonyl methoxyalkyl derivative of purines and pyrimidines26. It is taken up by both virally infected and uninfected cells and does not require the action of viral induced kinase to be converted its active moiety28,29. Cidofovir already exists in a monophosphorylated form because of its structure. Cellular enzymes convert cidofovir to the diphosphate form, which in turn is competitive inhibitor of viral DNA polymerase. There is a 25 to 50 fold selectivity of cidofovir diphosphate for the viral compared with the cellular DNA polymerase29.

Clinical pharmacology and toxicology: Cidofovir can be administered intravenously and topically by ocular implant. The terminal plasma half life is 2.6 hours and 90% of the drug is excreted in the urine. Renal tubular secretion contributes substantially to clearance. Cidofovir diphosphate has an intracellular half life of more than 48 hours, an important factor which confers a long lasting antiviral response that lasts for several days (or even weeks) after a single administration. This allows for infrequent dosing of the compound. The major adverse effect is nephrotoxicity, which results in renal tubular damage 30. Clinical status: Cidofovir is used for CMV retinitis in immunocompromised host resistant to, or intolerant to, ganciclovir and foscarnet. It can be given by intravenous or intravitreal route. Cidofovir also holds promise for the treatment of acyclovir resistant HSV infection, either by intravenous route or topically. It can be used for topical treatment of adenovirus keratoconjunctivitis and human papillomavirus infection in immunosuppressed and immunocompetent subjects32. Resistance: It has been observed in preliminary studies that mutation in the DNA polymerase of CMV mediates resistance to ganciclovir, foscarnet as well as cidofovir. Vidarabine: Vidarabine (9-B-D-ribofuranosyladenine, ara A, vira A) is a nucleoside purine ana-

336

logue with activity against all members of human herpes virus group. It is phosphorylated to its active triphosphate form, ara ATP by cellular kinases rather than by virus induced thymidine kinase so it is capable of inhibiting TK - (thymidine kinase) deficient mutants of HSV, which are resistant to acyclovir31. Several mechanism have been proposed to explain the inhibition of HSV replication by vidarabine which include selective inhibition of viral DNA polymerase by ara adenine triphosphate (ara ATP) due to competitive inhibition for the normal substrate, dATP (deoxyadenine triphosphate), inhibition of virus induced ribonucleotide reductase by either ara ATP or ara ADP that reduces the dATP pool. This ultimately inhibits DNA synthesis and selective incorporation of ara AMP into viral DNA causing a decrease in the rate of primer elongation and chain termination.

Clinical pharmacology toxicity: Vidarabine is readily deaminated to arabinoxyl hypoxanthine in vivo which has less antiviral activity than the parent compound. The plasma half life is 3-4 hr and nearly 60% of a dose is recovered in the urine, principally as arabinoxyl hypoxanthine. It is widely distributed in the body with levels in CSF approximately one third to one half of those in the serum. Vidarabine is relatively insoluble and its intravenous administration requires a large fluid load. The most common adverse effects of intravenous vidarabine have been gastrointestinal (nausea, vomiting and diarrhoea) and neurological (tremors, parasthesia, ataxia and seizures).

Clinical status: Vidarabine was initially used in the treatment of HSV encephalitis, neonatal HSV infection (1-5) and herpes zoster infection in immunocompromised host31. However acyclovir is found to be superior in treatment of HSV encephalitis and VZV infection, as well as in neonatal HSV infection1-5. The topical vidarabine ophthalmic preparation is efficacious in the treatment of HSV keratitis and can be used in persons where trifluridine cannot be used or is not tolerated 28-30. It is not effective in HIV infected persons with acyclovir resistant mucocutaneous HIV. Resistance: Isolation of resistant stains with mutation linked to polymerase gene shows that HSV specific DNA polymerase (pol) is a selective target of vidarabine32. Vidarabine resistance was subsequently

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mapped to a 0.8 kbp region within the pol gene21. There is cross resistance of vidarabine with other agents such as acyclovir.

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Trifluridine: Trifluridine (5 - trifluoromethyl - 2' deoxyuridine, Viroptic) is a halogenated, nucleoside analog. It is phosphylated to triphosphate form by cellular kinase and competitively inhibits DNA polymerase. Trifluridine is available as 1% ophthalmic solution and there is no significant systemic absorption. There is local irritation of eye following topical application. The main indication for topical trifluridine is for primary and recurrent HSV infections of the cornea and conjunctiva33. It is also used in the treatment of persistent cutaneous ulcers due to acyclovir resistant HSV infection in patients with AIDS34.

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Idoxuridine: Idoxuridine (5' iodo 2' deoxyuridine, stoxili, Herplex) is a pyrimidine nucleoside analogue. It is phosphorylated to its active form by cellular kinase. It acts as a competitive inhibitor of HSV, DNA polymerase and also acts as chain terminator. Idoxuridine is used as topical ophthalmic preparation. It can result in local irritation and inflammation after topical application including punctate keratopathy. Idoxuridine is used for topical treatment of HSV keratitis. HSV strains resistant to idoxuridine have been isolated from treated patients. Mutations in the DNA polymerase mediate this resistance. Drugs under trials: Fluorinated nucleoside analogues including fialuridine, fiacitabine have proved effective against a number of herpes virus in vitro and in animals. Efficacy against human infections not confirmed. Netuvidine, a 5alkynyl substituted pyrimidine analogue has been tried as selective inhibitor of VZV replication. Initial clinical studies in elderly suggested therapeutic benefits but toxicity after long term adnimistration was the reason to suspend the drug. Lobucavir, is currently under clinical evaluation for treating both VZV and HBV. REFERENCES 1.

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