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192 Combination effects of picornavirus replication inhibitors
191 Protective effect of bacterial p r e p a r a t i o n C M in experimental influenza infection J u l i a Serkedjieva, Emilia Ivanova Institute o f M i c r o b i o l o g y , Bulg Acad Sci, Sofia, Bulgaria The combined use of selective viral inhibitors and substances with i m m u n o p o t e n t i a t i n g effect is a promising a p p r o a c h in experimental antiviral c h e m o t h e r a p y . Previously it was shown that the cytoplasmic m e m b r a n e s of E. coli W F + stable p r o t o p l a s t type L - forms (CM) exhibited a pronounced stimulating effect on the cellular and h u m o r a l i m m u n e response in intact experimental animals. In the course of sublethal influenza infection with virus A/Aichi/2/68 (H3N2) in mice, C M applied i n t r a p e r i t o n e a l l y 7 days before virus inoculation in a single dose of 25 mg/kg stimulated the peritoneal m a c r o p h a g e and p o l y m o r p h o n u c l e a r functions in infected animals. The i m m u n o s t i m u l a t i n g and i m m u n o r e s t a u r a t i n g effect of C M was related to the presence of a lypopolysaccharide in the p r e p a r a t i o n . In the course of lethal influenza in-fection in mice with the same virus, C M applied in a single dose of 25 mg/kg 1 - 8 days before virus inoculation reduced mortality rate of experimental animals (protection index 59.5) and prolonged mean survival times (1.8 - 2.3 days). The protective effect was best expressed when the substance was inoculated 7 days before virus infection. The combined application of C M with r i m a n t a d i n e hydrochloride resulted in synergistic protective effect (protection index 88.8%). The protective effect of C M in experimental influenza infection in mice was a t t r i b u t e d mainly to its pronounced immunostimulating activity. O u r results clearly show that in experimental influenza infection in mice the a p p r o p r i a t e combined use of a selective antiviral agent with an i m m u n o m o d u l a t o r results in increased protection of infected animals.
192 COMBINATION EFFECTS OF PICORNAVIRUS REPLICATION INHIBITORS L. N i k o l a e v a a n d of M i c r o b i o l o g y ,
A. S. G a l a b o v . D e p a r t m e n t of U i r o l o g y , Institute B u l g a r i a n A c a d e m y of S c i e n c e s , S o f i a , B u l g a r i a
Uarious picornavirus replication inhibitors with known mec h a n i s m s of a c t i o n , i.e. g u a n i d i n e hydrochloride, HBB, S-7, a r i l done, d i s o x a r i l and enviroxime, as w e l l as r i b a v i r i n , were examined for their combination effects on poliovirus 1 (Mahoneg) replication in FL c e l l s . T h e p l a q u e - r e d u c t i o n test was used following t h e r e q u i r e m e n t s o f Prichacd & Shipman's model (ISBO) to analyze drug-drug interactions, revealing the dose-response surface. T h e r e s u l t s o b t a i n e d c o u l d be s u m m a r i z e d as f o l l o w s : i. s y n e r g y s m was observed when enviroxime and disoxaril, enviroxime and S-7, d i s o x a r i l a n d HBB, H B B a n d S - 7 w e r e c o m b i n e d ; 2. ribavirin produced antagonistic e f f e c t s w h e n c o m b i n e d w i t h all t e s t e d s u b s t a n ces; 3. e f f e c t s of t h e r e s t of c o m b i n a t i o n s could be character i z e d as a d d i t i v e o n e s . S y n e r g i s t i c combinations were tested on o t h e r m e m b e r s of t h e e n t e r o v i r u s g e n u s ( C o x s a c k i e el, E C H O 1 3 ) . A s r e g a r d to t h e p e r s p e c t i v e n e s s of the combination of enviroxime and disoxaril further experiments w e r e c e r r i e d o u t in o r d e r c r o s s resistance to be s t u d i e d . F o r t h a t p u r p o s e e n v i r o x i m e and disoxaril-resistant poliovirus mutants were selected. Resistance fol l o w e d o n l y t w o p a s s a g e s in t h e p r e s e n c e mE d i s o x a r i l a n d t e n p a ssages with enviroxime C~D ~ m o l / l e a c h ) . T h e e f f e c t s of b o t h of the substances were tested on the parental Mahoney strain and the resistant ones. Results revealed l a c k of c r o s s - r e s i s t a n c e which is v e r y e n c o u r a g i n g for further investigations.
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192 COMBINATION EFFECTS OF PICORNAVIRUS REPLICATION INHIBITORS L. N i k o l a e v a a n d of M i c r o b i o l o g y ,
A. S. G a l a b o v . D e p a r t m e n t of U i r o l o g y , Institute B u l g a r i a n A c a d e m y of S c i e n c e s , S o f i a , B u l g a r i a
Uarious picornavirus replication inhibitors with known mec h a n i s m s of a c t i o n , i.e. g u a n i d i n e hydrochloride, HBB, S-7, a r i l done, d i s o x a r i l and enviroxime, as w e l l as r i b a v i r i n , were examined for their combination effects on poliovirus 1 (Mahoneg) replication in FL c e l l s . T h e p l a q u e - r e d u c t i o n test was used following t h e r e q u i r e m e n t s o f Prichacd & Shipman's model (ISBO) to analyze drug-drug interactions, revealing the dose-response surface. T h e r e s u l t s o b t a i n e d c o u l d be s u m m a r i z e d as f o l l o w s : i. s y n e r g y s m was observed when enviroxime and disoxaril, enviroxime and S-7, d i s o x a r i l a n d HBB, H B B a n d S - 7 w e r e c o m b i n e d ; 2. ribavirin produced antagonistic e f f e c t s w h e n c o m b i n e d w i t h all t e s t e d s u b s t a n ces; 3. e f f e c t s of t h e r e s t of c o m b i n a t i o n s could be character i z e d as a d d i t i v e o n e s . S y n e r g i s t i c combinations were tested on o t h e r m e m b e r s of t h e e n t e r o v i r u s g e n u s ( C o x s a c k i e el, E C H O 1 3 ) . A s r e g a r d to t h e p e r s p e c t i v e n e s s of the combination of enviroxime and disoxaril further experiments w e r e c e r r i e d o u t in o r d e r c r o s s resistance to be s t u d i e d . F o r t h a t p u r p o s e e n v i r o x i m e and disoxaril-resistant poliovirus mutants were selected. Resistance fol l o w e d o n l y t w o p a s s a g e s in t h e p r e s e n c e mE d i s o x a r i l a n d t e n p a ssages with enviroxime C~D ~ m o l / l e a c h ) . T h e e f f e c t s of b o t h of the substances were tested on the parental Mahoney strain and the resistant ones. Results revealed l a c k of c r o s s - r e s i s t a n c e which is v e r y e n c o u r a g i n g for further investigations.
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