Vidarabine---Adenine arabinoside-

Vidarabine (also known as adenine arabinoside, or Ara-A) is a purine analog which inhibits the replication of a wide range of DNA and some oncogenic RNA viruses. The chemical name is 9-beta-D-arabinofuranosyl-adenine. Vidarabine was originally developed as an anti-cancer agent in 1960. Activity against DNA viruses was recognized in 1964. It was the first drug to have proven antiviral efficacy when given systemically. It is active against herpes simplex virus (HSV) and varicella-zoster viruses. 

Vidarabine was originally marketed by Parke-Davis (now a subsidiary of Pfizer) as Vira-As. Vidarabine ophthalmic ointment was also originally marketed by Parke-Davis, likewise under the brand name Vira-A; the product was licensed to Monarch Pharmaceuticals (now a subsidiary of King Pharmaceuticals, Bristol, TN, USA), which sold it until 2001, when it was withdrawn from the market. A fluorinated analog of vidarabine, fludarabine (Fludaras), is approved for the treatment of cancer. As vidarabine is no longer available in any form, having been replaced by aciclovir and other potent antiviral drugs active against herpesviruses, only a brief summary of the drug is included here. Details of vidarabine can be found in Kucers and Bennett.

MECHANISM OF DRUG ACTION

Vidarabine exerts its antiviral effect by inhibiting DNA synthesis. The drug is a prodrug, requiring sequential intracellular phosphorylation to the triphosphate, mediated exclusively by cellular enzymes, for it to be able to inhibit viral DNA polymerases. In this respect, vidarabine differs to, and lacks the selectivity of, aciclovir and penciclovir, as the phosphorylation of these last two antiviral drugs is initiated only by herpesvirus thymidine kinases, not cellular kinases. As a consequence, intracellular levels of vidarabine triphosphate are high in all cells, whereas intracellular levels of aciclovir and penciclovir triphosphates are high only in herpesvirus infected cells. Vidarabine triphosphate also inhibits mammalian cell DNA polymerases, but to a somewhat lesser degree than the virus-specified enzymes. Vidarabine is also incorporated into both cellular and viral DNA during DNA synthesis. In vivo, the major antiviral activity is mediated by arabinosyl hypoxanthine, which has considerably less activity than vidarabine . Arabinosyl hypoxanthine is 30-fold less active against herpesvirus replication than vidarabine. Studies in ducks infected with duck hepatitis B virus have shown that the mechanism of action of vidarabine against hepadnavirus replication is through inhibition of the viral DNA polymerase (which is a reverse transcriptase), resulting in a decrease in the ‘‘mature’’ forms of the viral DNA. There is, however, no effect on hepatitis B virus supercoiled DNA.

PHARMACOKINETICS

Vidarabine is rapidly deaminated to arabinosyl hypoxanthine within erythrocytes by the enzyme adenosine deaminase. Levels of arabinosyl hypoxanthine in erythrocytes parallel those in serum, and the cerebrospinal fluid levels are approximately 35% of serum levels. During a 12-hour infusion, arabinosyl hypoxanthine levels are in the range 3–6 mg/ml, and levels of the parent compound are less than 0.4 mg/ml. The predominant route of excretion is via the kidneys. There is no evidence of fecal excretion of the drug or its metabolite. Further details are provided in Kucers and Bennett.

TOXICITY

Although early animal studies with vidarabine suggested that it might be minimally toxic, as soon as human usage became common it became evident that vidarabine was associated with unacceptable toxicity, summarized briefly below. Dose-related gastrointestinal side-effects develop in approximately one-fifth of patients receiving the drug parenterally. Symptoms include anorexia, nausea, vomiting and diarrhea. Severe hepatic failure has been reported following vidarabine therapy in combination with prednisolone in the treatment of chronic hepatitis B infection. At doses higher than 15 mg/kg daily, pancytopenia and megaloblastic changes can occur. Hallucinations, confusion, psychosis, tremors, ataxia, myoclonus, dysarthria, aphasia, neuralgia, seizures and coma have all been reported in association with vidarabine therapy. A severe and prolonged polyneuropathy was reported in association with a 12-week course of vidarabine in patients with chronic hepatitis B infection. Weakness, fatigue, weight loss, rash, and thrombophlebitis at the site of intravenous injection can occur. Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone have been related to vidarabine therapy. Lacrimation, conjunctivitis, burning, irritation, keratitis, pain, photophobia, punctal occlusion and hypersensitivity have been reported with vidarabine ophthalmic ointment.