Vidarabine: A Preliminary Review of its Pharmacological Properties and Therapeutic Use

Academic Article

Abstract

  • Synopsis:Vidarabine2 is the first drug to become generally available in the USA for parenteral treatment of life-threatening or debilitating herpes simplex virus infections of man. For the past decade laboratory and clinical studies have been in progress to assess the pharmacology of the compound, its mechanism of action and its potential usefulness in clinical investigations. Currently, clinical usefulness has been established for herpes simplex infections of the eye and brain. Further studies in progress are evaluating the drug’s ability to prevent progressive disease from herpes zoster in the immunocompromised patient, reduce mortality and morbidity from neonatal herpes simplex virus infection and improve outcome of chronic hepatitis B infection. Pharmacology: Vidarabine is a purine nucleoside derivative developed specifically for therapy of life-threatening or severely debilitating human herpesvirus infections. In vitro, herpes simplex and varicella-zoster viruses are the most sensitive to drug; however, cytomegalovirus and Epstein Barr virus can be inhibited to some extent. Pharmacokinetic Studies: Peak plasma concentrations following a continuous 12-hour infusion of vidarabine at standard dosages of 10 to 15mg/kg/day are approximately 3 to 8μg/ml of arabinosyl hypoxanthine (the primary metabolite, formed by deamination) and about 0.2μg/ml of vidarabine. Arabinosyl hypoxanthine has antiviral activity, although less than the parent drug. It is found in the cerebrospinal fluid at a concentration of about one-third the plasma concentration. Topically applied vidarabine does not penetrate the anterior chamber of the eye to a significant extent, and this form of therapy is thus unsuitable for ‘deep’ eye infections. The kidney is the primary route of clearance. The drug and its metabolites can be found intracellularly for periods of up to several weeks following administration, although there is no evidence that extracellular accumulation occurs. Therapeutic Trials: Trials have been conducted for topical treatment of herpetic eye infections and with parenteral administration for herpes zoster and herpes simplex encephalitis. Topical treatment of herpes keratoconjunctivitis with 3 % vidarabine have demonstrated that the drug was at least as effective for healing as idoxuridine and trifluorothymidine. Importantly, many patients who experienced adverse effects because of idoxuridine administration (oedema, pain, burning, further injection) demonstrated prompt healing when switched to vidarabine. Similarly, parenteral vidarabine therapy appeared beneficial for uveal tract infection with herpes simplex virus. Parenteral trials of vidarabine have been conducted or are underway for herpes zoster in immunocompromised patients and herpes simplex encephalitis, neonatal herpes and chronic hepatitis B infections. In addition, small numbers of patients with progressive mucocutaneous herpes simplex and cytomegalovirus infections have received vidarabine. Only studies of herpes zoster and herpes simplex encephalitis have been completed to date. In these 2 diseases drug therapy had a beneficial effect on the disease course. Patients having herpes zoster who received treatment had accelerated clearance of virus from lesions, time to total pustulation and decreased new lesion formation. Pain was similarly qualitatively reduced at significant levels. Variables found to influence the healing process included the type of underlying disease, (lymphoproliferative malignancy versus other diseases requiring immunosuppressive therapy), age and duration of infection. Treatment of brain biopsy-proven herpes simplex encephalitis resulted in a statistically significant reduction in mortality from 70% (placebo) to 28 % 30 days following the onset of therapy. The level of consciousness at the time of brain biopsy and time to initiation of treatment were the major determinants of outcome with vidarabine treatment. Delaying therapy until coma ensues is associated with higher mortality and severe morbidity. Nearly 40 % of treated patients returned to an ‘adequate’ existence with 22% completely normal following therapy. The findings from this study of 28 patients have been verified in an additional 75 biopsy-proven and treated individuals in an open study. Completion of investigations of neonatal herpes simplex virus infection and herpes zoster may further expand the clinical usefulness of this drug. Side Effects: Intravenous administration of the drug at 10 to 15mg/kg/day for 5 to 10 days is associated with few adverse experiences if the patient has neither hepatic nor renal function compromised. Nausea, vomiting and/or diarrhoea occur in approximately 10 to 15 percent of all patients. Bone marrow toxicity is not apparent at these dosages but can be found with regularity if the dosage exceeds 25 to 30mg/kg/day. Dosage: Vidarabine is usually administered at a dosage of 15 mg/kg/day, by intravenous infusion only. Because of its low solubility, it should be dissolved in standard intravenous fluids in such a way so as not to exceed a vidarabine concentration of 450mg/L. For herpes simplex encephalitis the recommended duration of therapy is 10 days. © 1980, ADIS Press Australasia Pty Ltd.. All rights reserved.
  • Published In

  • Drugs  Journal
  • Digital Object Identifier (doi)

    Author List

  • Whitley R; Alford C; Hess F; Buchanan R
  • Start Page

  • 267
  • End Page

  • 282
  • Volume

  • 20
  • Issue

  • 4