Therapy of Experimental Herpes Simplex Encephalitis with Aciclovir in Mice

Abstract

This report is concerned with the capacities of aciclovir to protect mice challenged intracerebrally with multiple lethal doses of type 1 herpes simplex virus and to control multiplication of this virus in the brain. With treatment initiated 12 h after inoculation and continued for 4 consecutive days, aciclovir administered subcutaneously in daily doses ranging from 40 to 100 mg/kg led to 21-day survival rates of from 33 to 73% and reduced virus titers by 1 to 1,h x 4 logs on postchallenge day 8. The therapeutic accomplishments of the 100-mg/kg doses of aciclovir were comparable to those of 1,000-mg/kg doses of vidarabine (9-,B-Darabinofuranosyladenine); however, as measured by impact on body weight, aciclovir was better tolerated than vidarabine at these similarly effective doses.Aciclovir [ACV; 9-(2-hydroxyethoxymethyl)-guanine, or acycloguanosine] has been introduced recently as a potent and selective antiviral agent against herpes simplex virus type 1 (HSV-1) and 7,9,13,16). In vitro this compound also inhibits the multiplication ofvaricella zoster virus, cytomegalovirus, and B virus but has no effect on vaccinia virus, adenovirus type 5, and a range of ribonucleic acid viruses (16). ACV penetrates infected cells to a greater degree than uninfected cells (6). Once introduced into cells, it is converted to a monophosphate form by an HSV-specific thymidine kinase and eventually to a triphosphate form. ACV triphosphate then acts by inhibition of viral DNA polymerase. An additional selective advantage is that ACV triphosphate has a 30-foldgreater affinity for viral deoxyribonucleic acid polymerase than for cellular deoxyribonucleic acid polymerase in vitro (6,7). In the present study we evaluated the therapeutic efficacy of ACV for the herpes encephalitis by observing the capacities of ACV to protect mice inoculated intracerebrally with HSV-1 and to control the multiplication of this virus in the brain. More Forty-five mice inoculated with saline were divided into three equal subgroups which were treated as follows: (i) phosphate-buffered saline, 0.2 ml/day; (ii) ACV, 100 mg/kg per day; or (iii) ara-A, 1,000 mg/kg per day. Treatments were initiated 12 h after the inoculation of HSV-1 or saline and consisted of subcutaneous injections of two divided doses per day for 4 days. The mice were weighed on days 0, 2, 4, 8, 10, 14, and 16 after the inoculation to monitor weight change. The

Therapeutic activities of 1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)-5-iodocytosine and -thymine alone and in combination with acyclovir and vidarabine in mice infected intracerebrally with herpes simplex virus

“…The significant weight loss noted with ACV or ara-A at a dose of 400 mg/kg was consistent with that reported previously (18,21). Weight loss was also noted when FIAC or FMAU was given twice a day for 4 days at doses equal to or greater than 800 and 400 mg/kg per day, respectively.…”

Efficacy of acyclovir against mouse cytomegalovirus in vivo

“…Except for Epstein-Barr virus, these viruses share the property of expressing a virus-specified thymidine kinase that converts ACV to acycloguanosine monophosphate, which is further phosphorylated by host cell guanosine monophosphate kinase and other kinases (13) to its active form, acycloguanosine triphosphate, which inhibits the viral deoxyribonucleic acid (DNA) polymerase (7,9,10). Studies of HSV infections in mice treated with ACV have shown reduction in morbidity, mortality, and organ virus titers (8,12,16). We have found the in vitro susceptibility of mouse cytomegalovirus (MCMV) to ACV to be comparable to that reported for HSV types 1 and 2 and varicellazoster virus (Burns et al, unpublished data).…”

“…Hairless mice inoculated with HSV into the skin also experienced less severe local inflammation and reduced mortality with ACV treatment (12). In a mouse model of HSV encephalitis, ACV decreased mortality, brain virus titers, and weight loss (16). Also, if ACV treatments were started early enough and continued sufficiently long, the establishment of latent infection of dorsal root ganglia after skin inoculation was reduced.…”

Treatment of experimental herpes simplex virus encephalitis with (E)-5-(2-bromovinyl)-2'-deoxyuridine in mice

“…HSV infections in mice. These compounds are 9-1-Darabinofuranosyladenine (5,15,22,26,27), its 5'-monophosphate (19), 1-P-D-arabinofuranosylthymine (19), and 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine, acyclovir) (4,22,24). Akin to BVDU, all three arabinofuranosyl derivatives, as well as acyclovir, provide significant protection against HSV-1 encephalitis when administered s.c. or i.p.…”

“…However, these studies cannot be considered as truly representative for a systemic VOL. 22,1982 on April 29, 2019 by guest http://aac.asm.org/ Downloaded from therapy of herpetic encephalitis since, on the one hand, 5-trifluoromethyl-2'-deoxyuridine was injected i.c. (simultaneously with the virus inoculum) (6) and, on the other hand, the efficacy of 5-ethyl-2'-deoxyuridine was evaluated in mice which had been infected s.c. (7).…”