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Vidarabine
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Vidarabine
Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an antiviral drug which is active against herpes simplex and varicella zoster viruses.
Vidarabine is less susceptible to the development of drug resistant strains than other antivirals such as IDU, and has been used successfully in the treatment of IDU resistant viral strains. The half-life of the active triphosphate metabolite (ara-ATP) is three times longer in HSV-infected cells compared with uninfected cells, however the mechanism of selectivity is not known.
Vidarabine is an antiviral, active against herpes viruses, poxviruses, rhabdoviruses, hepadnaviruses and some RNA tumour viruses. A 3% ophthalmic ointment Vira-A is used in the treatment of acute keratoconjunctivitis and recurrent superficial keratitis caused by HSV-1 and HSV-2. Vidarabine is also used to treat herpes zoster in AIDS patients, reducing lesions formation and the duration of viral shedding. Many of the previous uses of vidarabine have been superseded by acyclovir, due to the hospitalisation required for intra venous dosing, and acyclovir has a higher selectivity, lower inhibitory concentration and higher potency. Toxic side effects are rare, but have been reported with high concentrations of vidarabine, such as nausea, vomiting, leukopenia and thrombocytopenia in patients receiving high intravenous doses daily.[citation needed]
It has a half-life of 60 minutes, and its solubility is 0.05%, and is able to cross the blood–brain barrier (BBB) when converted to its active metabolite.
Vidarabine works by interfering with the synthesis of viral DNA. It is a nucleoside analog and therefore has to be phosphorylated to be active. This is a three-step process in which vidarabine is sequentially phosphorylated by kinases to the triphosphate ara-ATP. This is the active form of vidarabine and is both an inhibitor and a substrate of viral DNA polymerase.
When used as a substrate for viral DNA polymerase, ara-ATP competitively inhibits dATP leading to the formation of "faulty" DNA. This is where ara-ATP is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can no longer to be built, destabilizing the strand. Vidarabine triphosphate (ara-ATP) also inhibits RNA polyadenylation; preventing polyadenylation essential for HIV-1 and other retroviruses; and S-adenosylhomocysteine hydrolase, preventing transmethylation reactions.[citation needed]
Uniquely to vidarabine, the diphosphorylated vidarabine (ara-ADP) also has an inhibitory effect. Other nucleoside analogs need to be triphosphorlated to give any antiviral effect, but ara-ADP inhibits the enzyme ribonucleotide reductase. This prevents the reduction of nucleotide diphosphates, causing a reduction of viral replication.
Vidarabine is more toxic and less metabolically stable than many of the other current antivirals such as acyclovir and ganciclovir. Viral strains resistant to vidarabine show changes in DNA polymerase. It is prone to deamination by adenosine deaminase to inosine. This metabolite still possesses antiviral activity, but is 10-fold less potent than vidarabine. 60% of vidarabine eliminated by the kidney is excreted as 9-β-D-arabinofuranosylhypoxanthine in the urine. Some breakdown of the purine ring may also occur, forming uric acid.
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Vidarabine
Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an antiviral drug which is active against herpes simplex and varicella zoster viruses.
Vidarabine is less susceptible to the development of drug resistant strains than other antivirals such as IDU, and has been used successfully in the treatment of IDU resistant viral strains. The half-life of the active triphosphate metabolite (ara-ATP) is three times longer in HSV-infected cells compared with uninfected cells, however the mechanism of selectivity is not known.
Vidarabine is an antiviral, active against herpes viruses, poxviruses, rhabdoviruses, hepadnaviruses and some RNA tumour viruses. A 3% ophthalmic ointment Vira-A is used in the treatment of acute keratoconjunctivitis and recurrent superficial keratitis caused by HSV-1 and HSV-2. Vidarabine is also used to treat herpes zoster in AIDS patients, reducing lesions formation and the duration of viral shedding. Many of the previous uses of vidarabine have been superseded by acyclovir, due to the hospitalisation required for intra venous dosing, and acyclovir has a higher selectivity, lower inhibitory concentration and higher potency. Toxic side effects are rare, but have been reported with high concentrations of vidarabine, such as nausea, vomiting, leukopenia and thrombocytopenia in patients receiving high intravenous doses daily.[citation needed]
It has a half-life of 60 minutes, and its solubility is 0.05%, and is able to cross the blood–brain barrier (BBB) when converted to its active metabolite.
Vidarabine works by interfering with the synthesis of viral DNA. It is a nucleoside analog and therefore has to be phosphorylated to be active. This is a three-step process in which vidarabine is sequentially phosphorylated by kinases to the triphosphate ara-ATP. This is the active form of vidarabine and is both an inhibitor and a substrate of viral DNA polymerase.
When used as a substrate for viral DNA polymerase, ara-ATP competitively inhibits dATP leading to the formation of "faulty" DNA. This is where ara-ATP is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can no longer to be built, destabilizing the strand. Vidarabine triphosphate (ara-ATP) also inhibits RNA polyadenylation; preventing polyadenylation essential for HIV-1 and other retroviruses; and S-adenosylhomocysteine hydrolase, preventing transmethylation reactions.[citation needed]
Uniquely to vidarabine, the diphosphorylated vidarabine (ara-ADP) also has an inhibitory effect. Other nucleoside analogs need to be triphosphorlated to give any antiviral effect, but ara-ADP inhibits the enzyme ribonucleotide reductase. This prevents the reduction of nucleotide diphosphates, causing a reduction of viral replication.
Vidarabine is more toxic and less metabolically stable than many of the other current antivirals such as acyclovir and ganciclovir. Viral strains resistant to vidarabine show changes in DNA polymerase. It is prone to deamination by adenosine deaminase to inosine. This metabolite still possesses antiviral activity, but is 10-fold less potent than vidarabine. 60% of vidarabine eliminated by the kidney is excreted as 9-β-D-arabinofuranosylhypoxanthine in the urine. Some breakdown of the purine ring may also occur, forming uric acid.
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