Combined treatment with 2'-nor-cGMP and ganciclovir against cytomegalovirus infection in a guinea pig model.
The combination 2'-nor-cGMP/DHPG at fixed ratios 1:5, 1:10 and 1:20 showed synergistic antiviral effects against GPCMV replication in vitro with CI value < 1. In vivo, a fixed ratio of 1:10 at three different dosage levels of 1.25/12.5 mg, 2.5/25 mg and 5/50 mg/kg/day 2'-nor-cGMP/DHPG combination showed only additive results when compared with each drug alone. However, synergistic antiviral effects were obtained when infected guinea pigs were treated with 2'-nor-cGMP/DHPG combination 2.5/10 mg/kg/day (1:4). A significantly lower GPCMV infectivity titer was noted in the salivary gland, lung and spleen of infected guinea pigs treated with the combination of 2'-nor-cGMP/DHPG 2.5/10 mg/kg/day, as compared to animals treated with a corresponding dose of each drug alone. In addition, GPCMV-infected animals treated with the latter combination showed increased body weight than when either drug was used alone. Histopathologically, each drug alone reduced the viral induced changes in the lung and spleen, but the combination therapy reduced these changes still further. Toxic changes seen in the kidney and bone marrow of infected animals treated with 2'-nor-cGMP, 2.5 mg/kg/day were not significantly increased when DHPG 10 mg/kg/day was added to the regimen. Therefore, combined treatment with 2'-nor-cGMP/DHPG in appropriate concentration is more helpful for acute cytomegalovirus infection in guinea pigs than when either drug was used alone.
Feng
J S
JS
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510.
Crouch
J Y
JY
Tolman
R L
RL
Lucia
H L
HL
Hsiung
G D
GD
D000208:Acute Disease; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects / Q000254:growth & development; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006168:Guinea Pigs; D009943:Organophosphorus Compounds / Q000627:therapeutic use*
D000998:Antiviral Agents; D009943:Organophosphorus Compounds; D006147:Guanine; C045511:9-((2-hydroxy-1,3,2-dioxaphosphorinan-5-yl)oxymethyl)guanine P-oxide; D015774:Ganciclovir