sorivudine and Acute-Disease

Bromovinyl-uracil (BVU) is the principal metabolite of sorivudine, a potent anti-zoster nucleoside. BVU binds to, and irreversibly inhibits, the enzyme dihydropyrimidine dehydrogenase (DPD). The objective of this study was to assess the time course of recovery of DPD activity after oral administration of sorivudine in patients with herpes zoster and to correlate restoration of DPD activity and levels of uracil with the elimination of sorivudine and its metabolite BVU from the circulation.. Sorivudine was given orally as 40 mg once-daily doses for 10 consecutive days to a total of 19 patients with herpes zoster. Serum sorivudine, BVU, and circulating uracil and DPD activity in peripheral blood mononuclear cells (PBMCs) were determined before, during, and after administration of sorivudine.. BVU was eliminated from the circulation within 7 days after the last sorivudine dose. DPD activity in PBMCs, which was completely suppressed in 18 of the 19 subjects and markedly suppressed in the remaining subject during administration of sorivudine, recovered to baseline levels within 19 days after the last dose of sorivudine in all subjects and within 14 days in all but one of the subjects. The restoration of DPD activity was temporally associated with elimination of BVU from the circulation. The elevated uracil concentrations produced by inhibition of DPD activity fell rapidly after cessation of sorivudine administration and also were temporally associated with elimination of BVU from the circulation. The time course of recovery of DPD activity in three patients with renal impairment was similar to that of the other subjects.. This study indicates that sorivudine therapy is associated with a profound depression of DPD activity. Recovery of DPD activity occurred within 4 weeks of the completion of sorivudine therapy, which indicates that fluorinated pyrimidines may be safely administered 4 weeks after completion of sorivudine therapy.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Analysis of Variance; Antiviral Agents; Arabinofuranosyluracil; Bromouracil; Chromatography, High Pressure Liquid; Dihydrouracil Dehydrogenase (NADP); Female; Herpes Zoster; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Oxidoreductases; Software; Uracil

The clinical efficacy and safety of sorivudine as treatment for acute cutaneous zoster in human immunodeficiency virus-infected adults was compared with that of acyclovir in a double-blinded randomized study. A total of 125 patients with laboratory-confirmed zoster rash present for < or =72 h were assigned treatment with either 40 mg of sorivudine once daily or 800 mg of acyclovir five times daily, both taken orally for 7 days. Patients were assessed daily until all lesions crusted and then monthly for 6 months for postherpetic neuralgia (PHN) and for 12 months for recurrent or new episodes of zoster. Sorivudine significantly shortened the median period of new vesicle formation from 3.0 to 4.0 days (log rank P = .0001). Sorivudine was effective regardless of duration of rash before treatment. Zoster recurrences and new episodes were experienced by fewer patients assigned sorivudine (11%) than acyclovir (26%, P = .037). No differences were seen in incidence, severity, or duration of either acute neuritis or PHN. Both treatments were well tolerated.

Topics: Acute Disease; Acyclovir; Adolescent; Adult; Antiviral Agents; Arabinofuranosyluracil; Double-Blind Method; Herpes Zoster; HIV Infections; Humans; Middle Aged; Patient Compliance

Four nucleoside analogues--acyclovir [9-(2-hydroxyethoxymethyl)guanine], bromovinyldeoxyuridine [(E)-5-(2-bromovinyl)-2-deoxyuridine], vinylarauracil 5-vinyl-1-beta-D-arabinofuranosyluracil and bromovinylarauracil [(E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil]--were compared in the therapy of acute keratitis induced in the rabbit cornea by inoculation of the KUPKA strain of herpes simplex virus type 1 (HSV-1). In comparison to placebo-treated animals, the drugs reduced the mean plaque counts in conjunctival swabs as follows: acyclovir to 0.16-1.73%, bromovinyldeoxyuridine to 0.02-0.25%, vinylarauracil to 0.55-5.96% and bromovinylarauracil to 0.12-3.39% of control values. Latency was established to a most limited extent in 1 or 2 out of 5 rabbits treated with vinylarauracil or bromovinylarauracil, respectively. One or 6 out of 84 or 98 explanted ganglion fragments (1.3 or 6%) were positive for HSV-1 as compared to 72 fragments out of 173 (43%) from placebo-treated rabbits. Acyclovir and bromovinyldeoxyuridine completely prevented latency.

Topics: Acute Disease; Acyclovir; Animals; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Chemical Phenomena; Chemistry; Keratitis, Dendritic; Rabbits; Simplexvirus; Uridine