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111 Comparative activity of selected antiviral compounds on In vitro replication of varicella zoster virus clinical strains
110 The Safety, P h a r m a c o k i n e t i c s , and A n t i - C M V a c t i v i t y of w e e k l y H P M P C in HIV p o s i t i v e p a t i e n t s e x c r e t i n g CMV. WL D R E W I, JP L A L E Z A R I I, E GLUTZERI; JC M A R T I N 2, PE F I S H E R 2, HS JAFFE a. i. Mount Zion M e d i c a l C e n t e r of UCSF, San F r a n c i s c o , CA, U.S.A., and 2. G i l e a d Sciences, Inc., F o s t e r City, CA, U.S.A. (S)-l-[3-Hydroxy-2-(phosphonylmethoxy)propyl] c y t o s i n e (HPMPC) is a n u c l e o t i d e a n a l o g w i t h potent in vitro and in vivo a c t i v i t y a g a i n s t CMV. Phosphorylation of HPMPC to its' active intracellular metabelite is i n d e p e n d e n t of virus i n f e c t i o n and a s s o c i a t e d w i t h p r o l o n g e d a n t i v i r a l effect. We c o n d u c t e d a p h a s e I/II study of w e e k l y i n t r a v e n o u s HPMPC in HIV i n f e c t e d p a t i e n t s w i t h a s y m p t o m a t i c shedding of CMV in u r i n e and semen. Five p a t i e n t s w e r e e n r o l l e d at each of four dose levels (0.5, 1.0, 3.0, and i0.0 mg/kg) and t r e a t e d for four weeks. N e p h r o t o x i c i t y was o b s e r v e d in 2 of 5 p a t i e n t s at the 3.0 m g / k g level after 6 and 14 doses r e s p e c t i v e l y , and was d o s e l i m i t i n g after 2 doses at the i0 mg/kg level. R e d u c t i o n of C M V titer in s e m e n a n d / o r c o n v e r s i o n to urine c u l t u r e n e g a t i v e was o b s e r v e d at b o t h the 3.0 a n d i0.0 m g / k g dose levels. These r e d u c t i o n s w e r e o b s e r v e d by viral t i t r a t i o n v i a p l a q u e assay as well as a b r a n c h e d c h a i n DNA assay. Nine a d d i t i o n a l p a t i e n t s then r e c e i v e d HPMPC at 5.0 m g / k g on a w e e k l y or every other w e e k s c h e d u l e w i t h c o n c o m i t a n t a d m i n i s t r a t i o n of p r o b e n e c i d , an inhibitor of organic anion transport which protects against HPMPC n e p h r o t o x i c i t y in animal models. P r e l i m i n a r y results i n d i c a t e a H P M P C p r o b e n e c i d d o s e d e p e n d e n t interaction. The c o m b i n a t i o n of c o n c o m i t a n t p r o b e n e c i d and e v e r y other w e e k dosing intervals a p p e a r s to s u b s t ~ n t i a l l y r e d u c e the n e p h r o t o x i c effects of HPMPC, w h i l e r e t a i n i n g anti C M V effect.
111 Comparative Activity of Selected Antiviral Compounds on In Vitro Replication of Varicella Zoster Virus Clinical Strains G. Andrei, R. Snoeck, M. Helsberg*, G. J~ihne* and E. De Clercq. Rega Institut,e for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium and SBU Antiinfectives - Research, G 838, Hoechst AG, D-65926 Frankfurt am Main, Germany Fifteen freshly isolated varicella zoster virus (VZV) strains were evaluated, in parallel with the reference strains expressing specific thymidine kinase ('IX) (Oka, YS) or deficient for viral TK (07-1 and YS-R),/n vitro in a plaque assay for their suscepttqaility to a broad range of antiviral substances including aeyclovir, BVDU, BVaraU, ganciclovir, FIAC, ara-T, ara-C, ara-A, foscarnet, phosphonoacetic acid, the acyclie nucleoside phosphonates HPMPC, I-IPMPA, cyclic HPMPC, 3-deaza-HPMPA, PMEA and PMEDAP, and the N7-isomeric acyclic nucleoside analogue 2242. For 13 out of the 15 clinical isolates the order of decreasing activity against VZV was BVaraU > BVDU > ara-C ~ ara-T ~ HPMPA ~ cyclic H P M P A ~ 3-deaza-HPMPA ~ 2242 ~ FIAC > acyelovir ,~ ganciclovir ~ HPMPC ~ cyclic HPMPC > PMEA ~ PMEDAP ~ foscarnet ~ phosphonoaeetic acid ~ ara-A. The two strains (isolated from the eerebrospinal fluid of an AIDS patient) that were shown to have a truncated Tit+ were dearly resistant to all the compounds that need the viral TK for their phosphorylation, while the sensitivity to the acyclie nueleoside phosphonates, foscarnet, phosphonoaeetie acid and ara-A remained unchanged. A slight (5-fold) increase was noted in the IC50 of compound 2242 for the TK-based drug-resistant VZV strains as compared to the sensitive VZV straln~. Also, ganeiclovir and FIAC showed a marked decrease in activity against these two strains, but not as pronounced as for the other TK-dependent drugs. From our results, it appears that the acyelie nueleoside phosphonates should be considered for the treatment of TK-based drug-resistant VZV infections.
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111 Comparative Activity of Selected Antiviral Compounds on In Vitro Replication of Varicella Zoster Virus Clinical Strains G. Andrei, R. Snoeck, M. Helsberg*, G. J~ihne* and E. De Clercq. Rega Institut,e for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium and SBU Antiinfectives - Research, G 838, Hoechst AG, D-65926 Frankfurt am Main, Germany Fifteen freshly isolated varicella zoster virus (VZV) strains were evaluated, in parallel with the reference strains expressing specific thymidine kinase ('IX) (Oka, YS) or deficient for viral TK (07-1 and YS-R),/n vitro in a plaque assay for their suscepttqaility to a broad range of antiviral substances including aeyclovir, BVDU, BVaraU, ganciclovir, FIAC, ara-T, ara-C, ara-A, foscarnet, phosphonoacetic acid, the acyclie nucleoside phosphonates HPMPC, I-IPMPA, cyclic HPMPC, 3-deaza-HPMPA, PMEA and PMEDAP, and the N7-isomeric acyclic nucleoside analogue 2242. For 13 out of the 15 clinical isolates the order of decreasing activity against VZV was BVaraU > BVDU > ara-C ~ ara-T ~ HPMPA ~ cyclic H P M P A ~ 3-deaza-HPMPA ~ 2242 ~ FIAC > acyelovir ,~ ganciclovir ~ HPMPC ~ cyclic HPMPC > PMEA ~ PMEDAP ~ foscarnet ~ phosphonoaeetic acid ~ ara-A. The two strains (isolated from the eerebrospinal fluid of an AIDS patient) that were shown to have a truncated Tit+ were dearly resistant to all the compounds that need the viral TK for their phosphorylation, while the sensitivity to the acyclie nueleoside phosphonates, foscarnet, phosphonoaeetie acid and ara-A remained unchanged. A slight (5-fold) increase was noted in the IC50 of compound 2242 for the TK-based drug-resistant VZV strains as compared to the sensitive VZV straln~. Also, ganeiclovir and FIAC showed a marked decrease in activity against these two strains, but not as pronounced as for the other TK-dependent drugs. From our results, it appears that the acyelie nueleoside phosphonates should be considered for the treatment of TK-based drug-resistant VZV infections.
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