Efficacy of (E)-5-(2-bromovinyl)-2′-deoxyuridine against different herpes simplex virus strains in cell culture and against experimental herpes encephalitis in mice

Reefschläger, J; Wutzler, Peter; Thiel, Klaus-Dieter; Bärwolff, D.; Langen, P.; Sprössig, M; Rosenthal, H. A.

doi:10.1016/0166-3542(82)90049-3

Cited by 21 publications

(17 citation statements)

References 24 publications

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“…However, two other compounds have emerged whose apparent lack of toxicity may also allow systemic use. Bromovinyldeoxyuridine (BVdU) (de Clercq et al, 1982); Reefschlager et al, 1982) and dihydroxypropoxymethylguanine (DHPG or 2'NDG) (Ashton et al, 1982) have both been reported to prevent herpes encephalitis in mice. However, the majority of published work to date has principally involved only the survival of infected mice as a measure of the effectiveness of chemotherapy and little quantitative data has been reported on the degree of inhibition of virus replication within the central nervous system (CNS) or the extent of tissue damage in the surviving animals.…”

Section: Introductionmentioning

confidence: 99%

A Quantitative Study of the Effects of Several Nucleoside Analogues on Established Herpes Encephalitis in Mice

Field

Anderson

Efstathiou

1984

Journal of General Virology

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SUMMARYMice with established herpes encephalitis were used to compare the effects of chemotherapy using three different nucleoside analogues. Encephalitis was produced by intranasal inoculation of a type 1 strain of herpes simplex virus. Without chemotherapy all mice died within 5 to 7 days of inoculation. Oral acyclovir (ACV) was a successful preventative measure if commenced within 2 days of inoculation but much less effective if the onset of treatment was further delayed. From the third day, when central nervous system infection had definitely become established, ACV only reduced mortality if given intraperitoneally (i.p.) at regular 6-hourly intervals. Comparison with bromovinyldeoxyuridine (BVdU) and the new nucleoside analogue dihydroxypropoxymethylguanine (DHPG) using the same 6-hourly i.p. regimen revealed that BVdU was poorly effective, despite better activity in vitro, whereas DHPG was the most successful. Virus was rapidly eradicated from all parts of the brain by DHPG therapy, and by day 10, no infectious virus remained in the brains of treated mice, no virus antigens were observed and no trace of virus DNA could be detected in neural tissues by Southern blotting.

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Section: Introductionmentioning

confidence: 99%

A Quantitative Study of the Effects of Several Nucleoside Analogues on Established Herpes Encephalitis in Mice

Field

Anderson

Efstathiou

1984

Journal of General Virology

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“…The drug has proven beneficial in herpesvirus infections in several animal models (4,6,7,11,16,18). In the only published human trial, oral BVdU limited the severity of herpes zoster in four patients, three of whom had underlying malignancy (3).…”

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confidence: 99%

“…These concentrations were 10-to 100-fold above usual serum concentrations after oral administration. (E)-5-(2-Bromovinyl)-2'-deoxyuridine compares favorably with currently used antivirals in terms of in vitro myelotoxicity and immunotoxicity.(E) -5 -(2-Bromovinyl)-2' -deoxyuridine (BVdU) is a synthetic pyrimidine deoxynucleoside which has demonstrated significant in vitro activity against herpes simplex virus type 1 and varicella-zoster virus (4,5).The drug has proven beneficial in herpesvirus infections in several animal models (4,6,7,11,16,18). In the only published human trial, oral BVdU limited the severity of herpes zoster in four patients, three of whom had underlying malignancy (3).…”

mentioning

confidence: 99%

Effects of (E)-5-(2-bromovinyl)-2'-deoxyuridine on proliferation of human fibroblasts, peripheral blood mononuclear cells, and granulocyte-monocyte progenitor cells in vitro

Wittek¹,

Cohen²,

Arvin³

et al. 1983

Antimicrob Agents Chemother

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Inhibition of human fibroblasts, granulocyte-monocyte progenitor cells, and lymphocytes was observed at (E)-5-(2-bromovinyl)-2'-deoxyuridine concentrations ranging from 21 to 197 p.g/ml. These concentrations were 10-to 100-fold above usual serum concentrations after oral administration. (E)-5-(2-Bromovinyl)-2'-deoxyuridine compares favorably with currently used antivirals in terms of in vitro myelotoxicity and immunotoxicity.(E) -5 -(2-Bromovinyl)-2' -deoxyuridine (BVdU) is a synthetic pyrimidine deoxynucleoside which has demonstrated significant in vitro activity against herpes simplex virus type 1 and varicella-zoster virus (4,5).The drug has proven beneficial in herpesvirus infections in several animal models (4,6,7,11,16,18). In the only published human trial, oral BVdU limited the severity of herpes zoster in four patients, three of whom had underlying malignancy (3).The selective antiviral activity of BVdU is at least partially attributed to its phosphorylation by virus-induced thymidine kinase and its relatively low affinity for cellular phosphorylases. BVdU, therefore, should be relatively nontoxic for animal cells (1, 2). Minimal toxicity has been suggested by in vitro studies in which a number of mammalian cell lines were used (4,5,15), but there have been few studies of the effects of BVdU on human cell lines (20).To investigate the possible toxicity of BVdU for human cells, we studied its effect on the growth of human foreskin fibroblasts (HFF) and granulocyte-monocyte colony-forming cells (CFU-C) and its effect on the proliferation of stimulated peripheral blood mononuclear cells (PBM) (Fig. 1)

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“…However, there have been some discrepancies in the efficacies of antiherpesviral drugs reported by different researchers. For example, treatment with a relatively high dose of either E-5-(2-bromovinyl)-2'-deoxyuridine (400 to 500 mg/kg per day) or brovavir (180 mg/kg per day) caused almost a complete cure rate in mice infected with HSV-1, irrespective of route of virus infection (2,10,12). On the other hand, we had found only a modest effect of brovavir and E-5-(2-bromovinyl)-2'-deoxyuridine in model infections with the VR-3 strain as a challenge virus (6).…”

Section: Discussionmentioning

confidence: 99%

“…However, therapeutic efficacies of the antiherpesviral bromovinyl nucleosides we observed were not as marked as those shown by Reefschlager et al (13) for brovavir and by De Clercq et al (2) and Park et al (10) for E-5-(2-bromovinyl)-2'-deoxyuridine. Reefschlager et al (12) also reported a marginal effect of E-5-(2-bromovinyl)-2'-deoxyuridine on intracerebral (i.c.) infection in mice with a strain of HSV-1.…”

mentioning

confidence: 99%

Effect of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (brovavir) on experimental infections in mice with herpes simplex virus type 1 strains of different degrees of virulence

Machida

Takezawa

1990

Antimicrob Agents Chemother

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In vivo antiherpesvirus effects of 1-,-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (brovavir) were tested in two mouse model infections with herpes simplex virus type 1 (HSV-1) strains which showed different degrees of virulence in mice. Successful efficacies of oral and intraperitoneal (i.p.) treatments with brovavir were demonstrated in both intracerebral and i.p. infections with the HSV-1 WT-51 strain of moderate virulence. However, only weak or modest effects of brovavir were observed against the two model infections with a highly virulent strain, HSV-1 VR-3. Brovavir was not effective in reducing mortality of mice infected i.p. with HSV-1 KOS, which exhibited the highest virulence in mice among HSV-1 strains used when inoculated i.p. However, the drug had a significant effect on intracerebral infection with the KOS strain. Efficacies of oral treatment with brovavir were almost equal to those of i.p. administration in the model infections. After intracerebral inoculation, the VR-3 strain grew in brains of mice at a higher rate than the WT-51 strain. By oral treatment with 50 mg of brovavir per kg twice daily, replication of the WT-51 strain in the brains was markedly suppressed and was eliminated after transient elevation of the titer. Growth of the VR-3 strain in the brains was simply delayed by the drug treatment. Thus, the antiviral efficacy of brovavir in mice was affected by the degree of virulence of the challenge virus strain used for infection.1-,-D-Arabinofuranosyl-E-5-(2-bromovinyl)uraciI (brovavir) is one of the most promising antiherpesviral agents under investigation (7). Previously, we showed in vivo antiviral activity of brovavir in mice infected with herpes simplex virus type 1 (HSV-1) (6). The in vivo effect was almost equivalent to that of E-5-(2-bromovinyl)-2'-deoxyuridine. However, therapeutic efficacies of the antiherpesviral bromovinyl nucleosides we observed were not as marked as those shown by Reefschlager et al.

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Efficacy of (E)-5-(2-bromovinyl)-2′-deoxyuridine against different herpes simplex virus strains in cell culture and against experimental herpes encephalitis in mice

Cited by 21 publications

References 24 publications

A Quantitative Study of the Effects of Several Nucleoside Analogues on Established Herpes Encephalitis in Mice

A Quantitative Study of the Effects of Several Nucleoside Analogues on Established Herpes Encephalitis in Mice

Effects of (E)-5-(2-bromovinyl)-2'-deoxyuridine on proliferation of human fibroblasts, peripheral blood mononuclear cells, and granulocyte-monocyte progenitor cells in vitro

Effect of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (brovavir) on experimental infections in mice with herpes simplex virus type 1 strains of different degrees of virulence

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