Antiviral agents vidarabine

Hudarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine. Its cytotoxicity is not well understood. It is rapidly dephospho-rylated at the cell membrane level and then rephos-phorylated intracellularly by deoxycytidine kinase to the active triphosphate derivative. It inhibits DNA polymerase and DNA primase. It is also incorporated into DNA and RNA. Hudarabine is administered intravenously by infusion over 30-120 min. It is eliminated by renal excretion with a terminal half life 10 hours. Adverse effects include myelosuppres-sion, nausea, vomiting, chills and fever. The number of CD4 positive cells is reduced and the incidence of opportunistic infections is increased. 

Fludarabine (Fludara) is a fluorinated purine analogue of the antiviral agent vidarabine. The active metabolite. 

Drug interactions There are no known drug interactions with Adagen. However, the antiviral agent vidarabine (Vira-A) is a substrate for ADA and 2 -deoxyco-formycin (Pentostatin) is a potent inhibitor of ADA. Thus the activities of these drugs and Adagen could be substantially altered if they are used in combination with one another. 

In addition to the use of ionizable groups, disruption of the crystal lattice can also result in a significant increase in aqueous solubility, as illustrated by the antiviral agent vidarabine (28). The 5 -formate ester derivative (29) of vidarabine is 67-fold more soluble in water than vidarabine itself and has been attributed to... 

Acyclovir-resistant HSV has been isolated from patients with AIDS. The primary mechanism of resistance appears to be a deficiency in viral thymidine kinase. Strategies that have been employed for management of severe acyclovir-resistant HSV infections include increasing the dose of acyclovir, discontinuing acyclovir, and use of an alternative antiviral agent. Vidarabine and foscarnet, because they do not require phosphorylation by thymidine kinase, are examples of potential alternative agents. A randomized comparison of foscarnet and vidarabine indicated that foscarnet is more effective and associated with fewer adverse reactions than vidarabine. ... 

Fludarabine phosphate, a fluorinated deamination-resistant nucleotide analog of the antiviral agent vidarabine (9-P-D-arabinofuranosyl-adenine), is active in CLL and low-grade lymphomas. After rapid extracellular dephosphorylation to the nucleoside fludarabine, it is rephosphorylated intracellularly by deoxycytidine kinase to the active triphosphate derivative. This antimetabolite inhibits DNA polymerase, DNA primase DNA ligase, and ribonucleotide reductase, and is incorporated into DNA and RNA. The triphosphate nucleotide is an effective chain terminator when incorporated into DNA, and the incorporation of fludarabine into RNA inhibits RNA function, RNA processing, and mRNA translation. 

Antiviral Agents. Although a number of antibiotics have been shown to have some sort of antiviral activity, only vidarabine [5536-17-4] (adenine arabinoside) is used clinically against viral infections at this time. As the need for new antiviral agents (qv) increases and new screening procedures are developed, one would expect the discovery of other new effective antiviral antibiotics that could be used safely in human therapy. 

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. 

The nucleoside vidarabine (ara-A) shows promise as an antiviral agent. Its structure is identical with that of adenosine (Section 27.24) except the D-arabinose replaces D-ribose as the carbohydrate component. Write a structural formula for this substance. 

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. 

At present, there are no antiviral compounds approved for use in animals (80MI10805). However, viral diseases of farm animals include such serious complaints as foot-and-mouth disease, and a new agent may very likely surface in the near future. Two possibilities are the following, which have already been approved for human use idoxuridine (53) and vidarabine (54). 

Vidarabine is an adenosine nucleoside obtained from cultures of Streptomyces antibloticus (56). Cellular enzymes convert vidarabine to mono-, di-, and triphosphate derivatives that interfere with viral nucleic acid replication, specifically inhibiting the early steps in DNA synthesis. This agent was used originally as an antineoplastic drug. Its antiviral effect is, in some cases, superior to that of idoxuridine or cytarabine. 

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