A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection

Whitley, Richard J.; Arvin, A; Prober, Charles G.; Burchett, Sandra; Corey, Lawrence; Powell, Dwight A.; Plotkin, S. A.; Starr, Stuart E.; Alford, Charles A.; Connor, James D.; Jacobs, Richard A.; Nahmias, André J.; Sj, Soong; Laughlin, Catherine A.; Benton, John W.; Lakeman, Alfred D.; Stagno, Sergio; Caddell, Gary; Watson, Neva B.

doi:10.1016/0020-7292(92)90997-w

Cited by 38 publications

(59 citation statements)

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“…Viral infections, including herpes simplex virus (HSV), enteroviruses, and parechoviruses, are also implicated in earlyonset neonatal sepsis and must be clinically differentiated from bacterial sepsis (42)(43)(44)(45)(46)(47)(48)(49)(50). There are other viruses associated with congenital infections, such as rubella virus, cytomegalovirus, lymphocytic choriomeningitis virus, and human immunodeficiency virus, for example.…”

Section: Pathogensmentioning

confidence: 99%

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Early-Onset Neonatal Sepsis

et al. 2014

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SUMMARY Early-onset sepsis remains a common and serious problem for neonates, especially preterm infants. Group B streptococcus (GBS) is the most common etiologic agent, while Escherichia coli is the most common cause of mortality. Current efforts toward maternal intrapartum antimicrobial prophylaxis have significantly reduced the rates of GBS disease but have been associated with increased rates of Gram-negative infections, especially among very-low-birth-weight infants. The diagnosis of neonatal sepsis is based on a combination of clinical presentation; the use of nonspecific markers, including C-reactive protein and procalcitonin (where available); blood cultures; and the use of molecular methods, including PCR. Cytokines, including interleukin 6 (IL-6), interleukin 8 (IL-8), gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), and cell surface antigens, including soluble intercellular adhesion molecule (sICAM) and CD64, are also being increasingly examined for use as nonspecific screening measures for neonatal sepsis. Viruses, in particular enteroviruses, parechoviruses, and herpes simplex virus (HSV), should be considered in the differential diagnosis. Empirical treatment should be based on local patterns of antimicrobial resistance but typically consists of the use of ampicillin and gentamicin, or ampicillin and cefotaxime if meningitis is suspected, until the etiologic agent has been identified. Current research is focused primarily on development of vaccines against GBS.

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Section: Pathogensmentioning

confidence: 99%

“…Importantly, neonates with disseminated HSV infection may not present with or develop skin vesicles, which could result in delayed diagnosis. Treatment of neonatal HSV infections with acyclovir intravenously is successful in reducing morbidity and mortality (46,47,77).…”

Section: Herpes Simplex Virusmentioning

confidence: 99%

Early-Onset Neonatal Sepsis

et al. 2014

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“…Encephalitis in newborns, for example, results in 15% mortality, and only 29% of survivors develop normally after acyclovir therapy (22). Also, for patients with less severe disease, an agent that will achieve a better reduction of lesion duration with episodic treatment beyond the 1 to 2 days' reduction achieved with current medications is urgently required (16).…”

mentioning

confidence: 99%

Potent In Vivo Antiviral Activity of the Herpes Simplex Virus Primase-Helicase Inhibitor BAY 57-1293

Betz

Fischer

Kleymann

et al. 2002

Antimicrob Agents Chemother

125

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BAY 57-1293 belongs to a new class of antiviral compounds and inhibits replication of herpes simplex virus (HSV) type 1 and type 2 in the nanomolar range in vitro by abrogating the enzymatic activity of the viral primase-helicase complex. In various rodent models of HSV infection the antiviral activity of BAY 57-1293 in vivo was found to be superior compared to all compounds currently used to treat HSV infections. The compound shows profound antiviral activity in murine and rat lethal challenge models of disseminated herpes, in a murine zosteriform spread model of cutaneous disease, and in a murine ocular herpes model. It is active in parenteral, oral, and topical formulations. BAY 57-1293 continued to demonstrate efficacy when the onset of treatment was initiated after symptoms of herpetic disease were already apparent.During the last 50 years, the treatment of herpesvirus infections has been continuously refined. Following the discovery of iodoxuridine in the mid-1950s and its successful demonstration as a topical therapeutic agent for herpes simplex virus (HSV) keratoconjunctivitis, vidarabine was licensed for systemic use and approved for the treatment of HSV encephalitis in 1978.Since it was first approved in 1981, the guanosine analogue acyclovir and later its L-valyl ester prodrug valacyclovir have been widely used in the treatment of HSV infections. Additional compounds used to treat HSV infections are famciclovir, the prodrug of penciclovir; ganciclovir; foscarnet; and cidofovir.Nevertheless, a high medical need exists for improved antiherpetic drugs for the treatment of severe disease. Encephalitis in newborns, for example, results in 15% mortality, and only 29% of survivors develop normally after acyclovir therapy (22). Also, for patients with less severe disease, an agent that will achieve a better reduction of lesion duration with episodic treatment beyond the 1 to 2 days' reduction achieved with current medications is urgently required (16). Furthermore, a drug which continues to show profound efficacy when given at later stages of herpetic disease would be a new and highly desired standard in the treatment of herpes (10). BAY 57-1293 (Fig. 1) is a member of the thiazolylsulfonamides, a recently discovered class of nonnucleosidic compounds with potent antiherpetic activity in vitro and in vivo, based on a novel mechanism of action (11a). It inhibited the replication of HSV type 1 (HSV-1) and HSV-2 in Vero cells with a 50% inhibitory concentration (IC 50 ) of 20 nM and a selectivity index of 2,500 and had about equal potencies against different strains and clinical isolates, while under the same assay conditions, acyclovir exhibited an IC 50 of 1 M and a selectivity index of 250. BAY 57-1293 targets the viral primase-helicase complex and inhibits its ATPase activity in a dose-dependent manner with an IC 50 of 30 nM. Resistant viral mutants exhibited amino acid substitutions in viral UL5 and/or UL52, which code for components of the viral primasehelicase complex. Accordingly, BAY 57-1293 also is acti...

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“…It reduced the spread of both herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections and decreased newlesion formation in the immunocompromised-patient population (22)(23)(24). Ara-A has also shown efficacy in the treatment of HSV-and VZV-induced encephalitis (20,24) and is equivalent to acyclovir [ACV; 9-(2-hydroxyethoxymethyl) guanine, Zovirax] in the management of neonatal herpes virus infections (21). However, its therapeutic use is complicated by problems of solubility and toxicity (6,24).…”

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confidence: 99%

Selective anabolism of 6-methoxypurine arabinoside in varicella-zoster virus-infected cells

Biron

Miranda

Burnette

et al. 1991

Antimicrob Agents Chemother

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). In this study, the mechanism of action of ara-M was explored. VZV-infected human fibroblasts selectively accumulated ara-M and its phosphorylated metabolites, whereas in uninfected fibroblasts or in those infected with a TK-deficient strain of VZV, there was virtually no cellular uptake of ara-M. The major intracellular metabolite of ara-M in VZV-infected cells was identified as the triphosphate of adenine arabinoside (ara-ATP). Appreciable levels of ara-ADP, ara-AMP, and ara-MMP were also detected. However, di-or triphosphorylated forms of ara-M were not detected. Moreover, in VZV-infected cells, the concentrations of ara-ATP which accumulated in the presence of ara-M were up to eightfold higher than those generated with ara-A itself. In contrast, in uninfected cells, the levels of ara-ATP which accumulated in the presence of ara-M were barely detectable. Clearly, Ara-M activation was dependent on the activity of the virus-encoded TK, while ara-A anabolism resulted primarily from the activity of host cell enzymes. Therefore, ara-M selectively generates the DNA polymerase inhibitor ara-ATP in the VZV-infected cell.The chemotherapy of herpes virus infections has evolved with the introduction of antiviral nucleoside analogs with increasing selectivity for virus-encoded target enzymes.Vidarabine (adenine arabinoside [ara-A]) was initially approved for the treatment of certain herpes virus infections. It reduced the spread of both herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections and decreased newlesion formation in the immunocompromised-patient population (22-24). Ara-A has also shown efficacy in the treatment of HSV-and VZV-induced encephalitis (20,24) and is equivalent to acyclovir [ACV; 9-(2-hydroxyethoxymethyl) guanine, Zovirax] in the management of neonatal herpes virus infections (21). However, its therapeutic use is complicated by problems of solubility and toxicity (6,24). ACV is a more potent nucleoside analog approved for the treatment of infections caused by HSV and VZV. ACV has been reported effective in the treatment of VZV infections in both the immunocompetent (9, 13) and the immunocompromised (18) host, although VZV is less susceptible than HSV to ACV inhibition in vitro (2, 4). A comparison of the efficacy of ara-A and ACV in VZV infections in immunocompromised patients showed ACV to be superior by several parameters (la, 18). In view of the comparable potency of ara-A and ACV against VZV replication in vitro, the superior efficacy and safety of ACV in the clinic is due in part to the selective activation of this nucleoside analog in virusinfected cells by the herpesvirus-encoded deoxythymidine kinase.

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A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection

Cited by 38 publications

References 0 publications

Early-Onset Neonatal Sepsis

Early-Onset Neonatal Sepsis

Potent In Vivo Antiviral Activity of the Herpes Simplex Virus Primase-Helicase Inhibitor BAY 57-1293

Selective anabolism of 6-methoxypurine arabinoside in varicella-zoster virus-infected cells

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