Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tolerance and pharmacokinetics of A515U, a xanthine oxidase-activated prodrug of acyclovir have been investigated in healthy volunteers and in two phase-I clinical studies in immunocompromised patients. In all cases the bioavailability of acyclovir following oral administration of A515U was substantially increased over that achieved in the same subjects with oral acyclovir itself. Plasma acyclovir levels were similar to those previously attainable only with intravenous acyclovir. This increase in bioavailability may permit reductions in the frequency of administration and extend the range of herpes virus infections amenable to oral therapy. A515U was very well tolerated, with no significant clinical adverse events being attributed to the drug.
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PMID:A515U: a prodrug of acyclovir with increased oral bioavailability. 379 61

Acyclovir (Zovirax) is a highly specific antiherpes virus agent. Extensive investigations of the pharmacokinetics in man have shown it to have a useful half-life of about three hours and to be largely excreted unchanged in the urine. Crystaluria can be avoided provided the patient is well hydrated and attention is paid to the dosing instructions especially in patients with renal failure. In vitro ED50s (the drug concentration inhibiting virus replication by 50%) bear some general relevance to effective plasma levels in man. A new prodrug of acyclovir, 2-amino-9-[2-hydroxyethoxy methyl]-9H-purine (A515U), which is converted to acyclovir by xanthine oxidase is rapidly absorbed from the human gut and converted to acyclovir. This prodrug provides the opportunity to design regimes that are more convenient for the patient and may be more effective than acyclovir itself in the therapy of the less sensitive herpes viruses (e.g. Epstein-Barr virus and the Cytomegalovirus).
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PMID:The clinical pharmacology of acyclovir and its prodrugs. 386 24

Famciclovir is the diacetyl 6-deoxy derivative of the active antiviral penciclovir that is for use in the treatment of infections caused by the herpes family of viruses. The major pathway of conversion is via di-deacetylation to BRL 42359, followed by oxidation to penciclovir. On oral dosing of famciclovir to humans, only penciclovir and BRL 42359 can be detected consistently in the plasma; thus, attention was focused on the oxidation reaction. This 6-oxidation occurred rapidly in human liver cytosol, had no requirement for cofactors, and followed simple Michaelis-Menten kinetics with a KM of 115 microM +/- 23 (N = 3). Using inhibitors of xanthine oxidase (allopurinol) and aldehyde oxidase (menadione and isovanillin), the relative roles of these enzymes in this process were determined. At a concentration of BRL 42359 that reflected plasma concentrations observed in humans (4 microM), both menadione (IC50 7 microM) and isovanillin (IC50 15 microM) caused extensive inhibition of the 6-oxidation reaction. In contrast, allopurinol caused no significant inhibition, confirming earlier in vivo work. At higher substrate concentrations (50 and 200 microM), the results with these inhibitors were broadly similar. These results provide strong evidence that aldehyde oxidase and not xanthine oxidase is responsible for the 6-oxidation of BRL 42359 to penciclovir in human liver cytosol, and this is likely to reflect the in vivo situation.
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PMID:Role of aldehyde oxidase in the in vitro conversion of famciclovir to penciclovir in human liver. 773 20

Synthesis of 6-deoxycyclopropavir (10), a prodrug of cyclopropavir (1) and its in vitro and in vivo antiviral activity is described. 2-Amino-6-chloropurine methylenecyclopropane 13 was transformed to its 6-iodo derivative 14 which was reduced to prodrug 10. It is converted to cyclopropavir (1) by the action of xanthine oxidase and this reaction can also occur in vivo. Compound 10 lacked significant in vitro activity against human cytomegalovirus (HCMV), human herpes virus 1 and 2 (HSV-1 and HSV-2), human immunodeficiency virus type 1 (HIV-1), human hepatitis B virus (HBV), Epstein-Barr virus (EBV), vaccinia virus and cowpox virus. In contrast, prodrug 10 given orally was as active as cyclopropavir (1) reported previously [Kern, E. R.; Bidanset, D. J.; Hartline, C. B.; Yan, Z.; Zemlicka, J.; Quenelle, D. C. et al. Antimicrob. Agents Chemother. 2004, 48, 4745] against murine cytomegalovirus (MCMV) infection in mice and against HCMV in severe combined immunodeficient (SCID) mice.
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PMID:Synthesis and antiviral activity of 6-deoxycyclopropavir, a new prodrug of cyclopropavir. 2241 49