sorivudine and Herpes-Zoster

Antiviral treatment of herpesvirus infections is rapidly changing since the advent of new drugs with improved oral availability. The efficacy of valaciclovir, the prodrug of aciclovir, and famciclovir, the prodrug of penciclovir, in the treatment of herpes genitalis and acute herpes zoster has been well documented in large clinical trials. Both drugs are effective on zoster-associated pain. Brivudin and sorivudine which are the most active compounds against varicella-zoster virus (VZV) in cell culture have also been successful in the treatment of herpes zoster. Aciclovir is still the standard therapy of severe herpes simplex virus (HSV) and varicella virus infections. In patients treated with aciclovir, the mortality of herpes encephalitis has been reduced to about 25%. The development of resistance against aciclovir and the other nucleoside analogues has not been a problem to date in the treatment of immunocompetent individuals. However, in immunocompromised patients, aciclovir-resistant HSV strains often emerge. In such cases, intravenous foscarnet is the current treatment of choice.

Topics: 2-Aminopurine; Acyclovir; Administration, Oral; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Chickenpox; Drug Resistance, Microbial; Encephalitis, Viral; Famciclovir; Herpes Genitalis; Herpes Labialis; Herpes Simplex; Herpes Zoster; Humans; Immunocompromised Host; Prodrugs; Simplexvirus; Valacyclovir; Valine

Sorivudine provides a unique nucleoside analog with significantly enhanced both in vitro and in vitro activity and enhanced oral bioavailability. Early indications from controlled studies indicate that sorivudine therapy is superior to acyclovir for the treatment of localized zoster in individuals with HIV infection and adults with chicken pox. However, these studies await peer evaluation. Importantly, recent experience in Japan indicates administration of sorivudine with 5-fluorouracil (5-FU) is contraindicated. Sorivudine inhibits dihydropyrimidine dehydrogenase, which is required for the metabolism of 5-FU. As a consequence, toxic levels of 5-FU accumulate in the plasma and have led to the deaths of nearly 30 patients in Japan. One might question, as these data unfold, the relative value of drugs with such enhanced in vitro activity and oral bioavailability as compared with standard therapeutic agents. Should accelerated healing occur, but not as dramatically as would have been anticipated from the in vitro data, unique approaches to the management of herpes zoster will need to be developed if further improvement is desired. Regardless, sorivudine appears superior to acyclovir for acceleration of cutaneous healing and, importantly, can be administered once daily in significantly smaller concentrations. These findings in and of themselves should allow for licensure of the compound in other developed societies.

Topics: Antiviral Agents; Arabinofuranosyluracil; Herpes Zoster; Humans

Topics: 2-Aminopurine; Acyclovir; Antiviral Agents; Arabinofuranosyluracil; Chickenpox; Drug Resistance, Microbial; Famciclovir; Herpes Simplex; Herpes Zoster; Humans; Valacyclovir; Valine

Herpes zoster is a serious medical problem, not only because of the discomfort associated with the acute rash, but also because of the potential for post-herpetic neuralgia. Acyclovir is currently the antiviral drug of choice for the treatment of herpes zoster. Efforts are underway to develop new drugs that have improved activity against varicella-zoster virus as well as more favorable pharmacokinetic properties. The goal of these efforts is to develop an orally administered antiviral drug that will accelerate the events of cutaneous healing as well as reduce the frequency and severity of post-herpetic neuralgia. Investigational drugs currently under evaluation include valaciclovir and famciclovir, the prodrugs of acyclovir and penciclovir, respectively. Two new uracil derivatives, sorivudine and BW882C87, with increased anti-varicella-zoster virus activity in vitro are also being studied.

Topics: 2-Aminopurine; Acyclovir; Antiviral Agents; Arabinofuranosyluracil; Drugs, Investigational; Famciclovir; Herpes Zoster; Humans; Prodrugs; Valacyclovir; Valine

The present randomized, double-blind, placebo-controlled, multicenter clinical trial was designed to compare the efficacy and tolerability of sorivudine [1-beta-D-arabinofuranosyl-E-(2-bromovinyl)uracil] and acyclovir for the treatment of dermatomal herpes zoster in human immunodeficiency virus (HIV)-seropositive patients. A total of 170 HIV-seropositive adults presenting with herpes zoster (confirmed by direct fluorescent-antigen testing and/or viral culture) were enrolled and randomized to receive a 10-day course of orally administered sorivudine (40 mg once daily plus acyclovir placebos) or acyclovir (800 mg five times daily plus sorivudine placebo). Patients were monitored daily to document the events of cutaneous healing, pain, zoster-related complications, and drug-related adverse events. Patients were reassessed on days 21 and 28 and then once monthly for 1 year. The primary efficacy endpoint was time to the cessation of new vesicle formation. Secondary efficacy endpoints included times to other events of cutaneous healing, resolution of pain, and frequency of dissemination and zoster recurrence. In a multivariate analysis, sorivudine was superior to acyclovir for reducing the times to the cessation of new vesicle formation (relative risk [RR] = 1.54, 95% confidence interval [CI] = 1.00 to 2.36; P = 0.049) and total lesion crusting (RR = 1.48, 95% CI = 1.07 to 2.04; P = 0.017). In a univariate analysis, there was a trend favoring sorivudine for the cessation of new vesicle formation (median of 3 versus 4 days; P = 0.07) and a significant advantage for time to total lesion crusting (median of 7 versus 8 days; P = 0.02). The time to the resolution of zoster-associated pain, the frequency of dissemination, and the frequency of zoster recurrence were not different between the two treatment groups. Both drugs were well tolerated. Sorivudine is an effective drug for the treatment of herpes zoster in HIV-infected patients and results in accelerated cutaneous healing when compared with acyclovir therapy.

Topics: Acyclovir; Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Antiviral Agents; Arabinofuranosyluracil; Double-Blind Method; Female; Herpes Zoster; Humans; Male; Middle Aged; Quality of Life; Recurrence; Treatment Outcome

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

Double-blind clinical trials were performed with a placebo to determine the optimum dose of YN-72 in patients with herpes zoster. YN-72 at 10, 50, and 100 mg was administered orally three times daily for 7 days. A total of 226 patients entered the present trial. Six of the 226 patients were excluded from statistical analysis of data. Furthermore, seven patients were excluded from the analysis for efficacy and usefulness, and included in the analysis for safety. The numbers of patients included in the analyses for efficacy and usefulness were 50 in the placebo group, 54 in the YN-72 30-mg/day group, 56 in the 150-mg/day group, and 53 in the 300-mg/day group. The numbers of patients included in analysis for safety were 53 in the placebo group, 58 in the YN-72 30-mg/day group, 56 in the 150-mg/day group and 53 in the 300-mg/day group. The effectiveness rate at the end of administration was 42.0% in the placebo group, 79.6% in the YN-72 30-mg/day group, 80.4% in the 150-mg/day group, and 61.5% in the 300-mg/day group. The rates in the YN-72 groups were significantly higher than in the placebo group. Evaluation at the end of the trials revealed that administration of YN-72 was effective. Among skin symptoms, administration of YN-72 accelerated the disappearance of erythema and vesicles and the formation of crust. Administration of YN-72 tended to accelerate the reduction and disappearance of pain. Reduction and disappearance in the YN-72 150-mg/day group occurred significantly earlier than in the placebo group (log-rank test).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Analgesia; Antiviral Agents; Arabinofuranosyluracil; Dose-Response Relationship, Drug; Double-Blind Method; Herpes Zoster; Humans; Placebos

A toxicokinetic study was performed using rats to investigate the possible mechanism of 18 acute deaths in Japanese patients with cancer and herpes zoster by interactions of the new oral antiviral drug, sorivudine (SRV), with one of the oral 5-fluorouracil (5-FU) prodrugs within 40 days after approval of the use of SRV. Tegafur, an anticancer 5-FU prodrug suggested to be used by most of the patients who died, and SRV were orally administered to rats simultaneously once daily. All of these rats died within 10 days, whereas rats given SRV or tegafur alone under the same dosage conditions showed no appreciable change over 20 days compared with controls. In the rats given both drugs, bone marrow and intestinal membrane mucosa were greatly damaged at an early stage of the coadministration, and before death, the animals showed marked decreases in white blood cell and platelet counts, diarrhea with bloody flux, and severe anorexia, as was also manifested by the patients who subsequently died. In the rats given both drugs for 6 days, extremely enhanced 5-FU levels were observed from the first day of administration in plasma and in all tissues examined, including bone marrow and intestines. The extreme enhancement of the tissue 5-FU levels was attributable to the facile inactivation by (E)-5-(2-bromovinyl)uracil (BVU) of hepatic dihydropyrimidine dehydrogenase (DPD), a key enzyme regulating the systemic 5-FU level in the rat and human. BVU, a major metabolite formed from SRV by gut flora, was found at considerable levels in the liver of rats orally administered SRV alone or SRV and tegafur, and there was a marked decrease in hepatic DPD activity. In the presence of NADPH, DPD purified from rat liver cytosol was rapidly and irreversibly inactivated by [14C]BVU as a suicide inhibitor with concomitant incorporation of the radioactivity into the enzyme protein, although SRV showed no inhibitory effect on DPD under the same conditions. Human liver DPD was recently demonstrated by us to be inactivated with BVU in a manner very similar to rat DPD.

Topics: Animals; Antimetabolites, Antineoplastic; Antiviral Agents; Arabinofuranosyluracil; Bromouracil; Cause of Death; Dihydrouracil Dehydrogenase (NADP); Drug Interactions; Fluorouracil; Half-Life; Herpes Zoster; Humans; Liver; Neoplasms; Oxidoreductases; Prodrugs; Rats; Tissue Distribution

Topics: Animals; Antiviral Agents; Arabinofuranosyluracil; Drug Design; Drug Interactions; Drug Therapy, Combination; Fluorouracil; Herpes Zoster; Humans; Japan; Prodrugs; Rats; Risk Assessment

Topics: Antiviral Agents; Arabinofuranosyluracil; Drug Approval; Government Agencies; Herpes Zoster; Humans; Japan; Social Responsibility

Susceptibilities to brovavir [1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)-uracil] and acyclovir of clinical isolates of varicella-zoster virus obtained from 58 patients with herpes zoster, included in a clinical trial of oral brovavir, were tested by a plaque reduction method. All 101 isolates were significantly susceptible to brovavir; 50% effective dose of brovavir for these isolates ranged between 0.6-4.0 ng/ml (average: 1.29 ng/ml). Brovavir was about 3,000 times more potent than acyclovir against these isolates. No marked change in the susceptibility of isolates from these patients during treatment with brovavir was observed.

Topics: Acyclovir; Adult; Antiviral Agents; Arabinofuranosyluracil; Cell Line; Herpes Zoster; Herpesvirus 3, Human; Humans; Uridine