Vidarabine toxicity

Epithelial keratitis that has not responded clinically to topical idoxuridine, or when ocular toxicity or hypersensitivity to idoxuridine has occurred. In a smaller number of patients resistant to topical vidarabine, trifluridine was also effective. 

Vidarabine (adenine arabinoside, ara-A) is phos-phorylated in the cell to the triphosphate derivative which blocks DNA synthesis by inhibiting DNA polymerase. It is indicated for infections with herpes simplex virus and varicella-zoster however its use has to a large extend been surpassed by aciclovir. It is administered topically or intravenously. It is inactivated rapidly by adenosine deaminase which for systemic use necessitates constant infusion of the drug. Vidarabine is the least toxic of the purine analogues. Nausea and vomiting are the most frequent adverse effects and neurotoxicity may occur. 

Since allopurinol is metabolized by the hepatic microsomal drug-metabohzing enzymes, coadministration of drugs also metabohzed by this system should be done with caution. Because allopurinol inhibits the oxidation of mercaptopurine and azathioprine, their individual administered doses must be decreased by as much as 75% when they are given together with allopurinol. Allopurinol may also increase the toxicity of other cytotoxic drugs (e.g., vidarabine). The actions of allopurinol are not antagonized by the coadministration of salicylates. 

Antiviral Efficacy and Clinical Use. Vidarabine (Vira-A) was the first systemic agent used to treat herpesvirus infections, including CMV, herpes simplex virus, and varicella-zoster virus.42 In the past, this drug was administered by continuous intravenous infusion to treat severe systemic infections caused by these viruses, but systemic use of vidarabine has been replaced by safer and less toxic agents. Vidarabine is currently used primarily to treat local viral infections of the eye (e.g., herpes simplex keratoconjunctivitis) it is applied topically by ophthalmic ointment to treat these infections. 

Vidarabine [vye DARE a been] arabinofuranosyl adenine, ara-A, adenine arabinoside) is one of the most effective of the nucleoside analogs and is also the least toxic. However, it has been supplanted clinically by acyclovir, which is more efficacious and safe. Although vidarabine is active against herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV), its use is limited to treatment of immunocompromised patients with herpes simplex keratitis or encephalitis, or VZV infections. Vidarabine, an adenosine analog, is converted in the cell to its 5 -triphosphate analog (ara-ATP), which is postulated to inhibit viral DNA synthesis. Some resistant herpes virus... 

Acyclovir Topical available outside of the United States. Zovirax Tablets, oral—400 mg, 800 mg capsule, oral—200 mg suspension, oral—200 mg/5 ml injectable— 50 mg/ml generic also available Topical acyclovir is similar in efficacy to idoxuridine, vidarabine, and trifluridine but less toxic to the eye. 

Acyclovir is less toxic to the ocular surface than idoxuridine, vidarabine, and trifluridine (Tabery, Grant). 

Trifluridine, which is active against Herpes simplex and Varicella zoster, has only been used in topical antiherpetic solutions. It is twice as potent as idoxuridine in 1% solution and 10 times more soluble. Trifluridine has been reported to heal dendritic keratitis faster than idoxuridine, to be as effective as vidarabine when used five times a day, to have no cross-toxicity with idoxuridine or vidarabine, to heal stromal corneal defects more effectively than idoxuridine, and to produce topical allergy, punctal narrowing, and punctal keratitis only rarely. Furthermore, it gives excellent results in herpetic ulcers previously treated with topical glucocorticoids and in idoxuridine-unresponsive ulcers. 

Intravenous vidarabine is effective in the treatment of kerato-uveitis in animals and man, and has been used intravenously to treat herpetic eye infections in man (1). It has also been used as an ointment for treating superficial keratitis that does not respond to idoxuridine, but it penetrates the eye poorly (2). It is no longer used because of unacceptable toxicity and inferior activity compared with newer drugs for Herpes simplex and Varicella zoster. Its rapid inactivation and poor solubihty are practical disadvantages. 

In the Irealmcnl of viral encephalitis, vidarabine had b be administered by constant flow intravenous infusion br-cause of its poor water solubility and rapid metabolic conin-sion to a hypoxanihinc derivative in vivo. These problem, coupled with the availability of le.ss toxic and more effedit.-agents, have caused intravenous- vidarabine to be withdrasn from the U. S. market. 

Vidarabine is a purine nucleoside analogue active against herpes viruses, influenza viruses, and some RNA viruses. Use of vidarabine for treatment of herpes simplex and varicella-zoster infections has largely been supplanted by acyclovir because of the superior efficacy, fewer adverse effects, and easier administration of the latter agent. Vidarabine has been associated with significant gastrointestinal, neurologic, and hematopoietic toxicities. Patients with renal insuffi-... 

The first systemically administered antiherpesvirus agent, vidarabine, was approved by the Food and Drug Administration (FDA) in 1977. However, its toxicities restricted its use to life-threatening infections of HSV and varicella-zoster virus (VZV). The discovery and development of acyclovir, approved in 1982, provided the first effective treatment for less severe HSV and VZV infections in ambulatory patients. Intravenous acyclovir is superior to vidarabine in terms of efficacy and toxicity in HSV encephalitis and in VZV infections of immunocompromised patients. Acyclovir is the prototype of a group of antiviral agents that are phosphorylated intraceUularly by a viral... 

Vidarabine, an antiviral agent (10 to 15 mg/kg/day for 5 to 10 days), is indicated in the treatment of herpes simplex virus encephalitis, neonatal herpes simplex virus infections, and herpes zoster in immunosuppressed patients. In addition, vidarabine (ophthalmic ointment 3% vidarabine monohydrate [equivalent to 2.8% vidarabine]) is indicated in the treatment of acute keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus types 1 and 2, or superficial keratitis caused by herpes simplex virus that has not responded to topical idoxuridine or when toxic or hypersensitivity reactions to idoxuridine have occurred. 

Vidarabine Vidarabine is an adenine analog and has activity against HSV, VZV, and CMV. Its use for systemic infections is limited by rapid metabolic inactivation and by marked toxic potential. However, it has been used intravenously for severe HSV infections, including those resistant to acyclovir, and it also prevents the dissemination of varicella-zoster virus in immunocompromised patients. Vidarabine is used topically for herpes keratitis, but it has no effect on genital lesions. Toxic effects with systemic use include gastrointestinal irritation, paresthesias, tremor, convulsions, and hepatic dysfunction. Vidarabine is teratogenic in animals. 

Trifluorothymidine is available as a 1% ophthalmic solution, which is effective in dendritic ulcers. Generally, a 1% eye solution of trifluorothymidine is well tolerated. Cross-hypersensitivity and crosstoxicity between trifluorothymidine, idoxuridine, and vidarabine are rare. The most frequent side effects are temporary burning, stinging, localized edema, and bone marrow toxicity. It is less toxic but more expensive than idoxuridine. Trifluorothymidine, when given IV, shows a plasma half-life of 18 minutes and is excreted in the urine either unchanged or as the inactive metabolite 5-carboxyuracil. 

There is some evidence to surest that if allopurinol and vidarabine (adenine arabinoside) are given together the toxicity of vidarabine may be increased. 

Two patients with chronic lymphocytic leukaemia taking allopurinol 300 mg daily developed severe neurotoxieity (eoarse rhythmie tremors of the extremities and facial muscles, and impaired mentation) 4 days after vidarabine was added for the treatment of viral infeetions. A retrospeetive search to find other patients who had taken both drugs for 4 days revealed a total of 17 patients, 5 of whom had experienced adverse reactions ineluding tremors, nausea, pain, itching and anaemia. Another possible case of neurological toxicity has also been reported. ... 

Collignon PJ, Sorrell TC. Neurolc ical toxicity associated with vidarabine (adenine arabino-side) ihQXQipy.AustNZJMed( 9Z >) 13,627-9. 

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