Vidarabine ara

Radiolabelled Solutes. 3H-hydrocortisone (New England Nuclear), -butanol (New England Nuclear), - C-octanol (New England Nuclear) and 3H-vidarabine (ARA-A, courtesy of Dr. D.C. Baker, University of Alabama) were used in the permeability experiments. These compounds were diluted with phosphate buffered saline (PBS, pH 7.3) to form stock solutions. The stock solutions were diluted within the donor compartments of the diffusion cells to have approximately 25 nCi/ml radioactivity per donor compartment. 

For HSV at least three mechanisms have been described that generate resistance to AC V deficiency or loss of viral TK activity, alteration in substrate specificity of the virus-encoded TK, and alteration in the substrate specificity of the viral DNA polymerase (1,8). Most of the ACVr mutants that have been isolated in vitro and recovered from clinical specimens are TK-deficient (TK). However, resistant clinical mutants that have an altered TK or altered DNA polymerase activity have occasionally been described too. Although TK mutants are crossresistant with drugs that also depend on viral TK for their activation (i.e., GCV, penciclovir and brivudin (BVDU), they remain sensitive to agents, such as PFA, vidarabine (Ara-A), and the acyclic nucleoside phosphonate (ANP) analogs. PFA, a pyrophosphate analog, is a direct inhibitor of the viral DNA poly-merase in which it binds to the site involved in releasing the pyrophosphate product of DNA synthesis. Phosphorylation of Ara-A to Ara-A triphosphate is carried out by cellular enzymes phosphorylation of ANP derivatives to their mono- and diphosphoryl derivatives is also carried out by cellular enzymes. 

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. 

Kurihara-Bergstrom, T., Flynn, G.L., and Higuchi, W.l. (1987). Physicochemical study of percutaneous absorption enhancement by dimethyl sulfoxide dimethyl sulfoxide mediation of vidarabine (ara-A). Permeation of hairless mouse skin, J. Invest. Dermatol, 89 274—280. 

The antiviral action of 5-iododeox5oiridine (lUdR) (4.9) has already been described in Section 4.0. It is widely prescribed for herpetic infections of the conjimctiva. Cytarabine ( Ara C ) (4./0), more selective, is used for severe generalized herpes in man (see Section 4.0). Vidarabine ( Ara A ) (4.JJ), a newer drug, has given useful clinical results in viral pneumonia and herpetic encephalitis (Section 4.0). The action of all these substances is to block stages in the synthesis of viral nucleic acids. 

Purine Nucleoside Derivatives. A number of purine nucleoside analogues are also found to be active against several DNA vimses (Fig. 3). The clinically active antiviral drug ara-A (9-P-D-arabinofuranosyladenine [5536-17-4] vidarabine, 23) is active against a number of DNA vimses in vivo and also inhibits certain RNA tumor vimses which repHcate through a DNA intermediate (43). Ara-A, was first synthesized in 1960 (44) and later... 

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. 

Viral DNA polymerase is an important catalyst for the synthesis of viral nucleic acids. DNA polymerase inhibitors have already been encountered as antitumor agents. Ara-A (9.5, vidarabine) is a DNA polymerase inhibitor that has demonstrated activity against herpes simplex virus type I (HSV-1) infections, responsible for cold sores on... 

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... 

In 1959, syntheses were reported of Ara C and, in 1960, of adenine arabi-noside (Ara A, vidarabine)11 (Figure 6.1). In 1961, Ara C was reported to have antitumour activity12 and later in the 1980s, both Ara A and Ara U were isolated from the gorgonian Eunicella eavo/ini.13 Today, Ara C is used to treat Hodgkin s lymphoma and acute myelocytic leukaemia,14 while Ara A is marketed as an antiviral drug. 

Vibramycin doxycycline. vidarabine [ban. inn. jan. usan) (adenine arabinoside Ara-A Vira-A ) is a purine nucleoside ANTIVIRAL isolated from the marine gorgonian Evnicella cavoUni and Streptomyces spp. Clinically, it may be used to treat herpes simplex and vaccinia infections. 

Showing that Mother Nature may follow chemists rather than the reverse, or conversely that it was always there but the natural products chemists were slow off the mark , arabinosyladenine (Ara-A or Vidarabine, 46, Figure 10) was synthesized in 1960 as a potential antitumor agent but was later produced by fermentation of Streptomyces antibioticus ViV A l>21> , and isolated, together with spongouridine, from a Mediterranean gorgonian (Eunicella cavolini) in 1984.°... 

The main metabolite, arabinosyl hypoxanthine (Ara-Hx) has approximately 1/20 the activity of vidarabine. In renal impairment, the excretion of Ara-Hx is decreased, requiring dose adjustment. Allopurinol, a xanthine oxidase inhibitor, may interfere with the metabolism of vidarabine (see also Figure 18). 

Vidarabine is deaminated quite rapidly by the enzyme adenine deaminase that is usually found in serum and RBC. Interestingly, this enzyme helps in the conversion of this drug , into its principal metabolite termed as arabinosyl hypoxanthine (ara-HX), which displays weak antiviral activity ... 

Vidarabine is deaminated rapidly by adenosine deaminase, which is present in serum and red blood cells. The enzyme converts vidarabine to its principal metabolite, arabinosyl hypoxanthine (ara-HX), which has weak antiviral activity (Fig. 43.8) (58). The half-life of vidarabine is approximately 1 hour, whereas ara-HX has a half-life of 3.5 hours. The drug is detected mostly in the kidney, liver, and spleen, because 50% of it is recovered in the urine as ara-HX. Levels of vidarabine in CSF fluid are 50% of those in the plasma. 

Vidarabine is an adenine arabinoside which shows in vitro activity against HSV, VZV and CMV. It is phosphorylated intracellularly by host enzymes to form ara-ATP which inhibits viral DNA polymerase. It is incorporated into both viral and cellular DNA and shows some animal teratogenicity [13],... 

Vidarabine 4.16) differs from adenosine in the same way that cytarabine differs from cytidine, namely the natural sugar has been replaced by arabinose. However, the anti-viral properties of vidarabine are more to the fore than any anti-cancer power, the exact opposite of cytarabine s properties. Vidarabine, also known as Ara A, is 9-j8-D-arabinofuranosyladenine and it has a reasonably high therapeutic index (Muller et al., 1977). Its most successful and spectacular application has been in herpes virus encephalitis, of which several thousands of cases break out in the United States each year, killing 70% of the sufferers... 

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