Further Characterization of the Potent and Prolonged Inhibition of Herpes Simplex Virus Replication in Human Cell Lines by Penciclovir

Abstract

SummaryThe replication of herpes simplex virus type 1 (HSV-1) or HSV-2 in MRC-5 cells infected at 0.01 pfu ceni and treated continuously for 72 h, was inhibited more efficiently by penciclovir than aciclovir (p =0.0001).However, multiple cycles of replication were required in order to distinguish the compounds. Virus from cultures treated for 72 h with either compound, at 3 or 10 /1g mr", was resistant to penciclovir and aciclovir (50% effective concentrations> 10 /1g mr"), but infectivity titres of supernatants from these aciclovirtreated cultures were higher than for penciclovir. Increased production of resistant virus in aclclovlrtreated cultures may be the consequence of the less potent inhibition of virus replication by aciclovir. Penciclovir caused prolonged inhibition of HSV-1 and HSV-2 replication in three human cell lines infected at 1 pfu celr" following treatment for 18 h, whereas virus replication resumed rapidly after withdrawal of aclclovir. Neither compound showed prolonged activity after 18 h treatment, when the multiplicity of infection was reduced to 0.01 pfu ceir'. This surprising observation prompted experiments testing the effect of repeated pulse treatment in cultures infected at low multiplicity. Penciclovir inhibited HSV-1 replication significantly more effectively than aciclovir in MRC-5 cells infected at 10-4 pfu ceni and treated daily for 6 h (p < 0.001, n =5) but only a trend was observed for HSV-2 (p =0.06, n =6).

The Influence of Cyclosporin Immunosuppression on the Efficacy of Famciclovir or Valaciclovir Chemotherapy Studied in a Murine Herpes Simplex Virus Type 1 Infection Model

“…More recent experiments in murine models for systemic HSV infection provided further weight for this hypothesis (Boyd et al, 1988;Sutton & Boyd, 1993;Ashton et al, 1994). Several workers have reported an effect of PCV in tissue culture that appeared to persist for up to several days after removal of the drug (Weinberg et al, 1992;Bacon & Schinazi, 1993;Standring-Cox et al, 1994;Bacon & Howard, 1996).…”

Pharmacokinetics of Penciclovir after Oral Administration of its Prodrug Famciclovir to Horses

“…, Shun-ichi NAGATA 2) , Takashi YAMANAKA 1) , Manabu NEMOTO 1) , Takashi KONDO 1) , Masahiko KUROSAWA 2) and Tomio MATSUMURA Equine herpesvirus type 1 (EHV-1) is a major causative agent of respiratory disease in horses and can also lead to abortion and neurological disease [1]. In particular, the recent increase in neurological EHV-1 outbreaks among horses in the U.S.A., the U.K. and Europe is of major concern to the horse industry worldwide, since affected animals often have a poor prognosis [7,8,[17][18][19][20].…”

“…However, it has been reported that the intracellular half-lives of penciclovir triphosphate are much longer than those of acyclovir triphosphate in human cells infected with herpes simplex virus type 1 (HSV-1), type 2 (HSV-2), or varicella-zoster virus (VZV) (10 hr vs. 0.7 hr, 20 hr vs. 1 hr, and 9.1 hr vs. 0.8 hr, respectively) [3,10,33]. Additionally, in both tissue culture [2] and animal infection [6,28], penciclovir has a more sustained antiviral effect than acyclovir against HSV-1 and -2, a finding that may be correlated with the difference in the stability of the 2 compounds in infected cells. If penciclovir triphosphate is more stable than acyclovir triphosphate in EHV-1-infected cells as well, then it might be possible to obtain therapeutic efficacy of famciclovir via a dosage regimen using lower dose than that required for valacyclovir therapy.…”