Effect of indomethacin on UV-induced recurrent genital HSV-2 disease in the guinea pig

174 E f f e c t of I n d o m e t h a c i n on U V - i n d u c e d r e c u r r e n t g e n i t a l ~SV-2 diseas$ in the guinea Pig. C. J. Harrison ~, ~. F. Bratcher ~, N. Bourne ~, ~.R. Stanberry ~, and D.I. Berns~ein ~, Children's Hosp. Res. Fnd. ~ and the Gamble Inst. Med. Res. ~, Cincinnati, Ohio. We have shown that recurrent genital h e r p e s s i m p l e x virus (HSV) disease can be induced in latently infected guinea pigs by ultraviolet (UV) irradiation. Previous studies have demonstrated that UV radiation exposure is associated with local increases in prostaglandin activity. We therefore studied the effects of i n d o m e t h a c i n (IND), a p r o s t a g l a n d i n i n h i b i t o r , on UV i n d u c e d reactivation of HSV. Primary genital infection was produced iD 26 Hartley guinea pigs by intravaginal inoculation with 5 X i0 D pfu/ml HSV-2 strain 333. On day i00 p o s t - i n o c u l a t i o n , animals were r a n d o m i z e d into two 5-day t r e a t m e n t groups (intramuscular IND at I0 mg/kg, or an e q u i v a l e n t v o l u m e of saline). On day i01, m e t a p h a n e a n e s t h e t i z e d animals were e x p o s e d to i0 min of U V - B light p r o d u c e d by t r a n s i l l u m i n a t o r s e m i t t i n ~ r a d i a t i o n between 280-320 nm with a peak output of 7000 uW/cm at 302 nm. Animals were scored for recurrences over the next 7 days. The I N D - t r e a t e d group had fewer total lesion days than the p l a c e b o group (25 vs. 3). Only 2/13 animals in the I N D - t r e a t e d group d e v e l o p e d r e c u r r e n t l e s i o n s c o m p a r e d to 11/13 a n i m a l s in the p l a c e b o r e c i p i e n t s , p<0.002. S e v e r e r e c u r r e n t d i s e a s e (more than one concurrent vesicle) occurred only in the placebo group. Mean lesion d a y s / a n i m a l for the 7 day o b s e r v a t i o n p e r i o d were 0.20±0.15 for placebo vs 0.02±0.07 for IND recipients, p<0.001. In this study, s y s t e m i c a l l y a d m i n i s t e r e d IND r e d u c e d the incidence of UV-induced recurrent disease in the guinea pig model.

175 Effect of Topical T r e a t m e n t w i t h HPMPC o n G e n i t a l Herpes Simplex V i r u s T y p e 2 (HSV-2) I n f e c t i o n s of G u i n e a Pigs or Mice. P.E. Vogt and E.R. Kern. Department of Pediatrics, University of Alabama School of Medicine, Birmingham, Alabama, 35294, USA. The Nucleoside Analogue (S)-l-(3-Hydroxy-2-Phosphonylmethoxypropyl) Cytosine (HPMPC) has been shown to be very active against HSV-1 or HSV-2 both in vitro and in vivo. The replication of HSV1 or HSV-2 in tissue culture cells is inhibited by about 1.0 ~g/ml of HPMPC, whereas Acyclovir (ACV) has an EDs0 of about 0.10-0.50 ~g/ml. The purpose of these studies was to evaluate the efficacy of topically applied HPMPC in animal models of primary genital HSV-2 infections. In guinea pigs, previous studies indicated toxicity with 5% HPMPC so treatment with 1% or 0.3% HPMPC three times daily or once daily was initiated 24 or 72H post inoculation. Therapy with 1% HPMPC beginning at 24H but not at 72H significantly altered lesion development. Vaginal viral replication was also significantly reduced with either 1% or 0.3% HPMPC initiated at 24H. In this study, HPMPC was more efficacious than 5% ACV. Since mice appear less susceptible to toxicity of HPMPC than guinea pigs, we then tested HPMPC in a genital HSV-2 infection of mice at 5%, 1% or 0.5% given three times daily, beginning 6 or 24H after virus inoculation. All concentrations of HPMPC tested reduced vaginal viral replication regardless of time of initiation of therapy. ACV at 5% also reduced vaginal viral replication, but not as effectively as HPMPC. These results indicate that topical therapy with 1%, 0.5%, or 0.3% HPMPC was more effective than 5% ACV in the treatment of genital HSV-2 infections of guinea pigs and mice and suggest that HPMPC should be considered for topical use in humans. 137