Treatment of Herpes Simplex Virus Types 1 and 2 Encephalitis in Mice with 9-β- d -Arabinofuranosyladenine

In vitro lymphocyte blastogenic responses to the commonly employed mitogens, phytohemagglutinin, pokeweed, and concanavalin A, were evaluated when adenine arabinoside (ara-A) in a concentration of 3 μg/ml was added to the culture materials. Similarly, blastogenic and cytotoxic responses to cell cultures persistently infected with herpes simplex virus 1, herpes simplex virus 2, and varicella-zoster virus were determined in the presence of ara-A. No depression of these cellular immune responses by ara-A was demonstrated. This was in contrast to the effect of cytosine arabinoside, which at a concentration of 3 μg/ml severely inhibited these immune responses. Further studies examined lymphocyte blastogenic responses to the mitogens and blastogenic and cytotoxic responses specific for the herpes group virus infecting patients who were subsequently treated with ara-A; determinations were made before, during, and after treatment. In vitro responses during and after treatment with ara-A were unchanged or often enhanced as compared to pretreatment values. Therefore, the antiviral chemotherapeutic agent, ara-A, does not appear to depress the host's cellular immune responses, which are vital to successful elimination of invading herpes group viruses.

Section: Resultsmentioning

confidence: 99%

Effects of Adenine Arabinoside on Cellular Immune Mechanisms in Humans

Steele

Chapa²,

Vincent³

et al. 1975

“…)ine has been shown to be an effective Weight loss was significant at daily doses of 200 gainst HSV encephalitis in hamsters (17), mg/kg for 4 days. The latter dose also effects a 18,19), and humans (2,20,21). A pilot moderate reduction in number of Jerne hemoy Ch'ien et al (2) In vitro antiviral activity of ACV was not determined.…”

Section: Tionmentioning

confidence: 99%

Therapy of Experimental Herpes Simplex Encephalitis with Aciclovir in Mice

Park

Pavan-Langston

McLean

et al. 1979

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

“…1-f-DArabinofuranosylcytosine (ara-C) has been reported to inhibit both HVH type 1 and type 2 in a variety of cell cultures (5, 10,34) and to be as effective as IUdR in the treatment of experimental HVH keratitis (14,33), and has been used in the treatment of HVH encephalitis in 588 KERN, OVERALL, AND GLASGOW HVH keratitis in hamsters (30) and HVH encephalitis in hamsters and mice (1, 19,29,31,32). Encouraging results have also been reported in the treatment of serious human HVH infections with ara-A (7).…”

mentioning

confidence: 99%

Herpesvirus hominis Infection in Newborn Mice: Comparison of the Therapeutic Efficacy of 1-β- d -Arabinofuranosylcytosine and 9-β- d -Arabinofuranosyladenine

Kern

Overall²,

Glasgow³

1975

Intranasal inoculation of newborn mice with Herpesvirus hominis type 2 provides an experimental infection that closely resembles disseminated herpesvirus infection of human newborn infants. After inoculation of mice, the virus multiplies in the respiratory tract and is disseminated through the blood to the liver and spleen and to the brain by both a viremia and nerve route transmission. Although therapy with 1-β- d -arabinofuranosylcytosine (ara-C) did not reduce final mortality, it did increase the mean survival time by 1 day. This effect on the mean survival time was associated with a 1-day delay in the appearance of herpesvirus in the blood, liver, and spleen and a reduction of virus replication in lung and brain for 1 day as compared with untreated control animals. Treatment with 9-β- d -arabinofuranosyladenine (ara-A) likewise had no effect on final mortality, but increased the mean survival time by 2 days. Therapy with ara-A delayed or suppressed virus replication in blood, lung, liver, spleen, and brain for 2 days. Although treatment with either ara-C or ara-A in this experimental H. hominis type 2 infection resulted in a temporary delay and/or suppression of viral replication in several target organs, neither compound was completely effective in inhibiting viral replication or in protecting animals from eventual death due to the infection.