Antiviral potencies against herpes simplex virus type 1 (HSV-1) of 1-ƒÀ-
Susceptibilities to brovavir [1-B-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. Brovavir [1-B-D-arabinofuranosyl-E-5-(2-bromovinyl) uracil; BV-araU] was re-ported to show marked antiviral activity against herpes viruses (3, 4). Particularly, its in vitro activity against varicella-zoster virus (VZV) was about 2,000 times more potent than that of acyclovir (6, 7). In addition, brovavir is very efficiently absorbed via the gastrointestinal tract and is only slightly degraded by metabolic enzyme(s) (5). Since there is now no oral antiviral drug approved for herpes zoster in Japan and the United States, these characteristics of brovavir make it very promising as a new chemotherapeutic antiviral agent for this disease.Recently, a clinical trial of oral brovavir in patients with herpes zoster was conducted in the departments of dermatology of 30 university-related hospitals by a well-controlled double-blind method. Adult immunocompetent patients within 5 days of onset of the skin eruption were subjects for the clinical study. Four groups of randomized patients received brovavir tablet at doses of either 0 (placebo control), 10, 50, or 100 mg three times a day for seven days. In nine medical facilities out of 30, which participated in the clinical study, viruses were isolated from blister fluid of the patients, and duration of virus shedding in the patients was determined in that study. Results on the clinical study and duration of virus shedding will be published elsewhere (8,11). This paper describes susceptibilities to brovavir and acyclovir of isolated VZV strains obtained from herpes zoster patients treated in Departments of Dermatology of the following nine universities;
We compared the selectivity of six anti‐varicella‐zoster virus (VZV) drugs, which are clinically available or of which clinical efficacy for the treatment of VZV infections has been reported. Sorivudine (BV‐araU) had the most potent anti‐VZV effect in the plaque inhibition assay, followed by brivudine (BVDU) and 5‐propynyl‐arabinofuranosyluracil (Pry‐araU). All test compounds, except vidarabine (AraA), had only a very weak effect on human embryonic lung cell growth. The selectivity indexes (ID50 for cell growth/ED50 for VZV plaque inhibition) of BV‐araU, BVDU, and Pry‐araU were > 1,000,000, 20,000, and > 10,000, respectively, while those of acyclovir and penciclovir ranged from 600 to 800. AraA was much less selective than any of the other drugs tested. We measured the amount of pH] thymidine incorporated into the acid‐insoluble fraction of VZV‐infected cells to determine the ability of these drugs to selectively inhibit viral DNA synthesis. [3H]Thymidine incorporation was markedly inhibited by all anti‐VZV compounds, except BVDU. Treatment of infected cells with drugs from 32 to 38 hr after infection inhibited the DNA synthesis to the same extent as VZV plaque formation, except that AraA inhibited the DNA synthesis at a lower dose than for VZV plaque formation. DNA synthesis in non‐infected growing cells was inhibited to the same extent as cell growth. A particularly high selectivity index for the inhibition of DNA synthesis was noted for BV‐araU, which was defined as the ratio of inhibitions of DNA synthesis in VZV‐infected and non‐infected. The highest selectivity indexes were recorded for BV‐araU > Pry‐araU > acyclovir ≥ penciclovir > AraA.
We studied antiviral effects of 1‐β‐d‐arabinofuranosyl‐5‐[(E)‐2‐bromovinyl]uracil (BV‐araU) and acyclovir against varicella‐zoster virus (VZV) multiplication varying the length or timing of drug exposure. First, residual anti‐VZV effect of drugs, exposed to cells for various periods followed by incubation in drug‐free medium, was determined by the plaque inhibition assay. None of the drugs showed activity when removed within 24 hr of incubation. Weakened efficacy of BV‐araU was seen in 2 days of treatment. When it was removed after 3 or 4 days, the ED50 was as low as that for cultures in which the drug was not removed. Still, plaque inhibition was not complete even at high concentrations. Acyclovir inhibited plaque formation only by 50% or less in 2 days of treatment. It gave a much higher ED50 in 3 days of treatment than that observed without drug removal. In the experiments, in which BV‐araU was added to VZV‐infected cells 1 day after infection, BV‐araU immediately suppressed increase in the number of infective centers at a concentration of 0.001 μg/ml, and reduced it at concentrations of 0.01 μg/ml or higher. The reduction of infective centers was seen with a dose‐dependent manner when added 2 or 3 days after infection. BV‐araU stimulated the decrease in the number of infective centers when added 4 days after infection. This inhibitory effect of acyclovir was very weak. Microscopic observations supported the above results. BV‐araU was still much superior to acyclovir in the anti‐VZV effect when the length and timing of drug exposure were varied.
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