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163 Effect of dexthan sulfate on experimental herpes simplex keratitis in rabbits
163 EFECT OF DEXTRIN SULFATE Oh E X P E R ~ v ~ T A L KERATITIS ~ RABBITS.
H~RPES S I M P ~
S. N. P a n c h e v a . I n s t i t u t e of M i c r o b i o l o g y , of Sciences, Sofia, B u l g a r i a .
Bulgarian
Academy
D e x t r a n sulfate has been shown to be a potent and sel e c t i v e i n h i b i t o r of the in v i t r o r e p l i c a t i o n of h u m a n imm u n o d e f i c i e n c y virus, h e r p e s s i m p l e x virus, c y t o m e g a l o v i r u s , v e s i c u l a r s t o m a t i t i s virus and other enveloped viruses in vitro. It seems that d e x t r a n sulfate m a y be a c a n d i d a t e for experimental trials to d e t e r m i n e its e f f i c a c y in i n h i b i t i n g also in vivo virus r e p l i c a t i o n . W e have now i n v e s t i g a t e d the a c t i v i t y of d e x t r a n su±fate on e x p e r i m e n t a l HSV-I keratitis in rabbits. D e x t r a n sulfate was applied immediateiy before virus inoculation and the t r e a t m e n t c o n t i n u e d for 10 days. It was achived s i g n i f i c a n t r e d u c t i o n in the s e v e r i t y and dur a t i o n of the o c u l a r i n f e c t i o n as well as in the virus shedd i n g in the t e a r film. D e x t r a n sulfate was also e f f e c t i v e in s u p p r e s s i n g the severity of c o n j u n c t i v i t i s . This activity was m o r e e x p r e s s e d with more frequent (twelve times d a i l ~ ~ h a n w i t h less f r e q u e n t (six times daily) therapy. T a k i n g into c o n s i d e r a t i o n the effectivity of the comp o u n d in the t r e a t m e n t of HSV-I k e r a t o c o n j u n c t i v i t i s in rabbits it seems w o r t h l u t h e r exploring dextran sulfate for its p o t e n t i a l in the t h e r a p y of h e r p e s v i r u s i n f e c t i o n s .
164 O-Alkyl and O-acyl prodrugs
of sorivudine
(BV-araU)
B. Machida, 1 N. Ashida, 1 K. Ijichi, 1 Y. Watanabe, 1, F. Kano, 2 and S. Sakata 2 Biology Lab. 1 and Chemistry Lab. 2, Yamasa Corp., Choshi, Japan BV-araU (i) has potent and selective anti-VZV effect, which is being administrated as a new antivir~l agent in Japan. 1 is metabolically more stable than BVDU, its deoxyuridine congener. However, BV-uracil, the major m e t a b o l i t e of I, is d e t e c t e d in blood and the urine in rats and humans after oral administration of i, probably due to d e g l y c o s y l a t i o n by the action of enterobacteria. To seek m e t a b o l i c a l l y more stable p r o d r u g s of i, a series of its alkyl prodrugs and the corresponding acyl derivatives were synthesized and evaluated them by determining blood l e v e l of 1 in m i c e a n d t h a t of 1 and B V - u r a c i l , the u r i n a r y excretion in rats after oral doses and their anti-HSV-i effect in mice. 5'-O-Alkyl BV-araUs were resistant to the degradation by entero-bacteria, and 5 ' - a l i p h a t i c esters were less stable than the c o r r e s p o n d i n g 5 ' - O - a l k y l prodrugs. 5 ' - O - E t h y l B V - a r a U as well as its propyl and butyl congeners, 3'-O-ethyl, 5'-aliphatic and some 5'-aromatic esters of 1 gave blood concentrations of 1 as high as those after oral administration of 1 in mice. 5'-0Ethyl BV-araU also showed m a r k e d anti-HSV-I effects against a couple of model i n f e c t i o n s in mice e q u i v a l e n t to those of i. Metabolism in rats indicated that 5'-O-Ethyl BV-araU, but not 5'O-benzyl derivatives, displayed good bioavailability and showed b e t t e r m e t a b o l i c s t a b i l i t y than I. Thus, 5 ' - O - E t h y l B V - a r a U seems to be an excellent prodrug of 1 with metabolic stability.
131
H~RPES S I M P ~
S. N. P a n c h e v a . I n s t i t u t e of M i c r o b i o l o g y , of Sciences, Sofia, B u l g a r i a .
Bulgarian
Academy
D e x t r a n sulfate has been shown to be a potent and sel e c t i v e i n h i b i t o r of the in v i t r o r e p l i c a t i o n of h u m a n imm u n o d e f i c i e n c y virus, h e r p e s s i m p l e x virus, c y t o m e g a l o v i r u s , v e s i c u l a r s t o m a t i t i s virus and other enveloped viruses in vitro. It seems that d e x t r a n sulfate m a y be a c a n d i d a t e for experimental trials to d e t e r m i n e its e f f i c a c y in i n h i b i t i n g also in vivo virus r e p l i c a t i o n . W e have now i n v e s t i g a t e d the a c t i v i t y of d e x t r a n su±fate on e x p e r i m e n t a l HSV-I keratitis in rabbits. D e x t r a n sulfate was applied immediateiy before virus inoculation and the t r e a t m e n t c o n t i n u e d for 10 days. It was achived s i g n i f i c a n t r e d u c t i o n in the s e v e r i t y and dur a t i o n of the o c u l a r i n f e c t i o n as well as in the virus shedd i n g in the t e a r film. D e x t r a n sulfate was also e f f e c t i v e in s u p p r e s s i n g the severity of c o n j u n c t i v i t i s . This activity was m o r e e x p r e s s e d with more frequent (twelve times d a i l ~ ~ h a n w i t h less f r e q u e n t (six times daily) therapy. T a k i n g into c o n s i d e r a t i o n the effectivity of the comp o u n d in the t r e a t m e n t of HSV-I k e r a t o c o n j u n c t i v i t i s in rabbits it seems w o r t h l u t h e r exploring dextran sulfate for its p o t e n t i a l in the t h e r a p y of h e r p e s v i r u s i n f e c t i o n s .
164 O-Alkyl and O-acyl prodrugs
of sorivudine
(BV-araU)
B. Machida, 1 N. Ashida, 1 K. Ijichi, 1 Y. Watanabe, 1, F. Kano, 2 and S. Sakata 2 Biology Lab. 1 and Chemistry Lab. 2, Yamasa Corp., Choshi, Japan BV-araU (i) has potent and selective anti-VZV effect, which is being administrated as a new antivir~l agent in Japan. 1 is metabolically more stable than BVDU, its deoxyuridine congener. However, BV-uracil, the major m e t a b o l i t e of I, is d e t e c t e d in blood and the urine in rats and humans after oral administration of i, probably due to d e g l y c o s y l a t i o n by the action of enterobacteria. To seek m e t a b o l i c a l l y more stable p r o d r u g s of i, a series of its alkyl prodrugs and the corresponding acyl derivatives were synthesized and evaluated them by determining blood l e v e l of 1 in m i c e a n d t h a t of 1 and B V - u r a c i l , the u r i n a r y excretion in rats after oral doses and their anti-HSV-i effect in mice. 5'-O-Alkyl BV-araUs were resistant to the degradation by entero-bacteria, and 5 ' - a l i p h a t i c esters were less stable than the c o r r e s p o n d i n g 5 ' - O - a l k y l prodrugs. 5 ' - O - E t h y l B V - a r a U as well as its propyl and butyl congeners, 3'-O-ethyl, 5'-aliphatic and some 5'-aromatic esters of 1 gave blood concentrations of 1 as high as those after oral administration of 1 in mice. 5'-0Ethyl BV-araU also showed m a r k e d anti-HSV-I effects against a couple of model i n f e c t i o n s in mice e q u i v a l e n t to those of i. Metabolism in rats indicated that 5'-O-Ethyl BV-araU, but not 5'O-benzyl derivatives, displayed good bioavailability and showed b e t t e r m e t a b o l i c s t a b i l i t y than I. Thus, 5 ' - O - E t h y l B V - a r a U seems to be an excellent prodrug of 1 with metabolic stability.
131