Parenteral Acyclovir Therapy for Herpesvirus Infections in Man

Selby, Peter J.; Jameson, Beryl; Watson, J. Graham; Morgenstern, G. R.; Powles, R; Kay, H. E. M.; Thornton, Ruth B.; Clink, H.M.; McElwain, T. J.; Prentice, H. G.; Ross, M G; Corringham, Robert; Hoffbrand, A. V.; Brigden, D.

doi:10.1016/s0140-6736(79)92281-5

Cited by 168 publications

(24 citation statements)

References 11 publications

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“…SVV has been shown to code for a specific thymidine kinase which phosphorylates ACV (K. K. Biron both groups. These results of ACV treatment are consistent with those reported by Selby et al (20) in immunosuppressed human patients with diagnosed VZV infection. ACV treatment of those patients brought relief from pain, regression of skin lesions and inhibition of development of new skin lesions.…”

Section: Resultssupporting

confidence: 92%

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Acyclovir treatment of experimental simian varicella infection of monkeys

Soike¹,

Felsenfeld²,

Gerone³

1981

Antimicrob Agents Chemother

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Replication of simian varicella virus (SVV) in Vero cell cultures was inhibited by acyclovir, 9-(2-hydroxyethoxymethyl)guanine (ACV), at a concentration of 10 ,ug/ml in culture medium: Intravenous administration of ACV at 10 mg/kg twice a day for 10 days or 15 mg/kg three times a day for 5 days to patas monkeys (Erythrocebus patas) beginning 48 h after SVV inoculation blocked the appearance of rash and other clinical symptoms but did not affect viremia. ACV treatment of African green monkeys (Cercopithecus aethiops) at 10 mg/kg twice a day by intravenous injection beginning 24 or 72 h after SVV inoculation and continuing for 10 days had no effect on clinical symptoms, including the development of rash, or on the appearance of viremia. The minimal therapeutic results could be due to the observation that doses of 10 or 15 mg/kg produced plasma levels of ACV which were lower than 5 ,ug/ml, the concentration that inhibited SVV multiplication in vitro, and decayed rapidly.The susceptibility of members of the herpesvirus group to inhibition in vitro by acyclovir [ACV; 9-(2-hydroxyethoxymethyl) guanine] has been reported to vary from the highly susceptible herpes simplex virus (HSV) type 1 to the markedly resistant cytomegalovirus (4). Clinical isolates of varicella-zoster virus (VZV) were shown to be inhibited by a mean 50% infectious dose of 3.75 uM for ACV, compared with 0.15 ,uM for HSV type 1 and 1.02 ,uM for HSV type 2. The greater resistance of VZV to ACV was confirmed by Biron and Elion, whoe reported a mean 50% infectious dose of 3.65 t,M (1). This level of inhibition in vitro is clinically attainable and suggests potentially effective therapeutic treatment of human varicella infection (1, 4).Experimentally induced HSV infections of various tissues in vivo have been effectively treated with ACV. These have included keratitis in rabbits (12), lip and skin lesions in mice (13,15), and encephalitis (19) and ganglionic infections in mice (10,13,14,17

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Section: Resultssupporting

confidence: 92%

“…Three of the four monkeys starting treatment at 24 h VOL. 20,1981 on May 12, 2018 by guest http://aac.asm.org/ Downloaded from Table 3 reports the results of radioimmunoassays performed by P. de Miranda of Burroughs Wellcome Laboratories on sera from monkeys receiving ACV. Plasma levels of ACV were determined in relation to time after i.v.…”

Section: Resultsmentioning

confidence: 99%

Acyclovir treatment of experimental simian varicella infection of monkeys

Soike¹,

Felsenfeld²,

Gerone³

1981

Antimicrob Agents Chemother

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“…ACV, BVDU, and FIAC appear at least as, if not more, promising than ara-A for the systemic treatment of VZV infections. In preliminary (uncontrolled) clinical tnrals, these compounds were found to block the progress of the infection promptly after treatment was started (8,24 Gibson, and P. J. Gerone, Antiviral research, in press).…”

Section: Discussionmentioning

confidence: 99%

In vitro susceptibility of varicella-zoster virus to E-5-(2-bromovinyl)-2'-deoxyuridine and related compounds

Clercq¹,

Descamps²,

Ogata³

et al. 1982

Antimicrob Agents Chemother

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The in vitro susceptibility of eight strains of varicella-zoster virus (VZV) to E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was examined in human embryonic fibroblasts by the following techniques: inhibition of focus formation by either cell-free VZV (4-day assay) or cell-associated VZV (2-day assay), inhibition of viral antigen formation (2-day assay), and inhibition of viral cytopathogenicity (15-day assay). The 50% inhibitory dose (ID50) of BVDU ranged from 0.001 ,ug/ml (2-day assay) to 0.01 ,ug/ml (15-day assay). BVDU appeared highly selective in its anti-VZV activity since even at concentrations as high as 100 ,ug/ml, BVDU did not markedly affect the viability of the host cells. The ID50 of BVDU for VZV was comparable to that of IVDU (E-5-(2-iodovinyl)-2'-deoxyuridine). Both drugs inhibited the replication of VZV at a much lower concentration than did other antiviral compounds such as iododeoxyuridine, ethyldeoxyuridine, arabinosylcytosine, arabinosyladenine, phosphonoacetic acid, iododeoxycytidine, and acycloguanosine. BVDU and IVDU were virtually inactive against a thymidine kinasedeficient VZV mutant, suggesting that phosphorylation by the viral enzyme is responsible, at least in part, for the selective anti-VZV activity of the compounds.Several nucleoside analogs exert a selective inhibitory effect on the replication of herpes simplex virus (HSV), be it type 1 (HSV-1) or type 2 (HSV-2). Typical examples are 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine,), 5,6-dihydro-5-aza-2'-deoxythymidine, and the halogenovinyl derivatives BVDU [E-5-(2-bromovinyl)-2'-deoxyuridine] and IVDU [E-5-(2-iodovinyl)-2'-deoxyuridine] (11). The selective antiherpesvirus activity of these compounds is, to an important extent, dependent on their phosphorylation by the HSV-induced thymidine kinase (TK). The latter differs from the host TK not only in physical properties but also in substrate specificity (4). The viral enzyme has a broader substrate affinity than the host enzyme, which means that some nucleoside analogs which are not recognized as substrate by the host TK may act as substrate for the viral TK; hence, their phosphorylation will be confined to the virus-infected cell.Since varicella-zoster virus (VZV), like HSV, is capable of inducing a specific TK (5, 6, 12-14, 21) which resembles HSV-induced TK in substrate specificity, one may expect compounds like ACV, ara-T, IDC, AIU, and FIAC, which are all effective against HSV, to be similarly effective against VZV. Indeed, in vitro inhibition of VZV replication has been noted for ACV (2, 7), ara-T (20), IDC (12), AIU (15), and FIAC (18) at concentrations which were not toxic for the host cells. We have now extended these observations to the 5-halogenovinyl-substituted 2'-deoxyuridines BVDU and IVDU. These compounds were found to inhibit VZV replication in human diploid cells at a concentration of 0.001 to 0.01 ,ug/ml, which is comparable to the minimum effective dose reported for FIAC (18) but much lower than the concentrations at which the other compounds, i.e., ACV, AIU,...

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“…The introduction of acyclovir into clinical practice was a useful development in the management of herpesvirus infections (Selby et al, 1979). The drug has been proved to be a highly effective treatment for herpes simplex (HSV) and varicella zoster virus (VZV) infections both in immune compromised and immune competent patients (Meyers et al, 1982;Balfour et al, 1983;Prober et al, 1982;reviewed by Fiddian & Grant, 1985;Prentice & Hann, 1985;Strauss, 1985;Gore & Selby, 1987).…”

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confidence: 99%

The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation

Selby

Powles²,

Easton³

et al. 1989

Br J Cancer

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Summary Eighty-two patients were randomly allocated to receive intravenous acyclovir 5 mg kg 1t.d.s. for 23 days followed by oral acyclovir 800mg 6-hourly for 6 months or matching placebos after allogeneic bone marrow transplantation. Herpes simplex and varicella zoster virus infections were significantly reduced during the period of administration of acyclovir. No reduction in cytomegalovirus infection was demonstrated. The drug was not toxic.The introduction of acyclovir into clinical practice was a useful development in the management of herpesvirus infections (Selby et al., 1979). The drug has been proved to be a highly effective treatment for herpes simplex (HSV) and varicella zoster virus (VZV) infections both in immune compromised and immune competent patients (Meyers et al., 1982;Balfour et al., 1983;Prober et al., 1982; reviewed by Fiddian & Grant, 1985;Prentice & Hann, 1985;Strauss, 1985;Gore & Selby, 1987). The efficacy and lack of toxicity of acyclovir has led to its use to prevent reactivation of herpesvirus infections. It is effective in the prophylaxis of HSV reactivation both in the immune competent patient with, for instance, recurrent genital herpes simplex and in the immune compromised patient, after, for instance, allogeneic bone marrow transplantation (Saral et al., 1981;Gluckman et al., 1983;Wade, 1984; Fiddian & Grant, 1985;Prentice & Hann, 1985; Straus, 1985;Gore & Selby, 1987). However, information about the prophylaxis of VZV infection is much less complete.The concentrations of acyclovir that are required to inhibit VZV in vitro are much higher than those required to inhibit HSV. This observation, together with the limited absorption of acyclovir when given by the oral route (Brigden & Whiteman, 1985), led to doubt about the effectiveness of acyclovir for the oral treatment or prophylaxis of VZV. However, it has been shown that oral acyclovir in high doses is effective in shortening the duration of VZV infections in immune competent patients (Peterslund, 1985;McKendrick et al., 1986).Reactivation of both HSV and VZV after bone marrow transplantation are a common source of morbidity. Up to 70% of patients who are seropositive for HSV infection develop reactivations and 40% of patients get herpes zoster or varicella (Saral et al., 1981;Locksley et al., 1985). However, evidence that long-term oral acyclovir will prevent the development of VZV was inconclusive. We have therefore carried out a prospective randomised double blind trial of intravenous acyclovir given for 23 days followed by oral acyclovir for 6 months in patients following allogeneic bone marrow transplantation. (Freedman & White, 1976).Acyclovir or placebo was administered to adults at a dose of 5mg kg-1 in 100 ml of normal saline infused over 1 h, given 8-hourly starting on the day before transplantation and continuing for 23 days. At that point adults received 800mg tablets 6-hourly for 6 months. Children less than 12 years of age received 250 mg m-2 acyclovir intravenously followed by 400mg orally 6-hourly. Patients wer...

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Parenteral Acyclovir Therapy for Herpesvirus Infections in Man

Cited by 168 publications

References 11 publications

Acyclovir treatment of experimental simian varicella infection of monkeys

Acyclovir treatment of experimental simian varicella infection of monkeys

In vitro susceptibility of varicella-zoster virus to E-5-(2-bromovinyl)-2'-deoxyuridine and related compounds

The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation

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