Chemotherapy of Genital Herpes Simplex Virus Type 2 Infections of Female Hamsters

Abstract

The antiviral activity of 1-,3-n-arabinofuranosylcytosine (ara-C, cytarabine, Cytosar), 5-iodo-2'-deoxyuridine (IdUrd), 9-,8-D-arabinofuranosyladenine (ara-A), and disodium phosphonoacetate (PAA) have been compared in herpes simplex virus type 2 (HSV-2)-infected primary rabbit kidney cells and in female hamsters with genital HSV-2 infection. In vitro, ara-C and IdUrd were more active than ara-A, and PAA was least active. In female hamsters with genital HSV-2 infection, intravaginal treatment with PAA or ara-A was more effective than either ara-C or IdUrd. PAA was more active than ara-A when treatment was initiated early (1 h) after infection. The activity of PAA was greatly reduced if initiation of treatment was delayed for 24 h. Both PAA and ara-A reduced the virus titers of the vagina and protected hamsters from death when the drugs were given by either the intravaginal or subcutaneous route, with intravaginal treatment being more effective.Genital herpesvirus infections, primarily caused by herpes simplex virus type 2 (HSV-2), are transmitted by venereal contact (9, 26). The infection can be painful and recurrent. If lesions are present late during the gestation period, the neonate is at high risk, resulting in disease with high morbidity and mortality (25). Furthermore, HSV-2 has been implicated in the etiology of cervical carcinoma (2,4,23).At the present time, there is no effective treatment for genital HSV infections. However, several agents with antiherpes activity in other systems have been studied in herpes genitalis. Topical application of certain heterocyclic dyes, followed by exposure to light, has been proposed as a method for treating this disease (5). However, in subsequent studies with proflavine (34), or in a double-blind study with neutral red (24), it was not possible to demonstrate efficacy.We have recently described the experimental genital infection of female hamsters with HSV-2 (30). In the studies described herein, several drugs with reported antiherpes activity have been compared in vitro and in female hamsters with genital HSV-2 infection. MATERIALS AND METHODSVirus. Stocks of HSV-2 (strain 35D) were supplied by L. T. Chien, University of Tennessee. The virus had a titer of 7.5 x 105 to 1.0 x 0l plaque-forming units per 0.5 ml on primary rabbit kidney monolayers.In vitro antiviral activity. Contiguous monolayers of primary rabbit kidney cells were infected by incubating 0.5 ml of stock virus with drained monolayers (60-mm plastic petri dishes, Falcon) for 60 min at 370C. The monolayers were washed and refed with 4.5 ml of Eagle medium containing 3% fetal bovine serum. The drugs were prepared in Hanks solution, and 0.5 ml of the appropriate dilution was added to each plate, resulting in the concentrations indicated. The cultures were harvested to -70°C when approximately 50 to 75% of the cells in the control cultures showed evidence of cytopathology. The virus titers of the frozen-thawed cultures were determined by the plaque method on rabbit kidney monolayers.Genital infection of femal...

Effect of trisodium phosphonoformate in genital infection of female guinea pigs with herpes simplex virus type 2

“…Furthermore, chronic latent infection with spontaneously recurring genital lesions develops in animals surviving the primary disease (23). Several antiviral substances which have been effective in animal models for cutaneous or genital ItSV infections (21,24), have not shown any therapeutic effect in well controled clinical trials in humans with cutaneous or genital HSV infections (1,25). It should, however, be pointed out that the treatment in these animal models has not been therapeutical since it Mways has started either a few hours post infection or shortly before the disease became evident.…”

Antiviral activity of some .beta.-diketones. 4. Benzyl diketones. In vitro activity against both RNA and DNA viruses

“…This oil was placed on a Si02 (1 kg) column packed wet with EtOAc-hexane (1:4) and eluted with the same solvent in 500-mL fractions. Fractions [7][8][9][10][11][12][13][14][15] were combined and concentrated to give an oil (17.5 g). This material was crystallized from hexane-Et¡0 to give the desired product (6.5 g, 26%), mp 65-66 °C.…”

Treatment of Experimental Herpesvirus Infections with Phosphonoformate and Some Comparisons with Phosphonoacetate

“…In contrast, treatment initiated later in the course of infection in guinea pigs, i.e., 24 h after infection, failed to retard the development of the lesions. In both genital HSV model infections PF appeared to be as effective as PA. PA has also been reported to be efficacious against a genital HSV infection ofhamsters (15), skin lesions induced by HSV and vaccinia virus in mice and rabbits (2,17), and herpes keratitis in rabbits (3,17). The data reported in this paper suggest that PF would also be effective in these other model infections.…”