Efficacy of ganciclovir in combination with other antimicrobial agents against cytomegalovirus in vitro and in vivo.
In MRC-5 cell cultures, the efficacy of the acyclic nucleoside ganciclovir (GCV) against human cytomegalovirus (CMV) was unaffected when combined with either amphotericin B (AMP B), ketoconazole (KCZ), dapsone (DAP), or trimethoprim/sulfamethoxazole (TMP/SMX). When differences in 3-dimensional plots for antiviral activity and cytotoxicity of GCV alone and in combination were compared, the anti-CMV activity of GCV (IC50 8 microM, 5-9 microM range) was not affected by concentrations of up to 10 microM AMP B, 1000 microM KCZ, 100 microM DAP or 320 microM TMP/SMX (higher concentrations could not be tested due to cytotoxicity). In Swiss Webster mice, the anti-CMV activity of GCV was also unaffected when administered in combination with any of the four other antimicrobial agents against murine CMV. GCV (s.c.) alone had an ED50 of 7 mg/kg (2-12 mg/kg range) which was unaffected by daily doses of 1 mg/kg AMP B (i.p.), 60 mg/kg KCZ (i.p.), 32 mg/kg DAP (p.o.) or 80/400 mg/kg TMP/SMX (p.o.). These results suggest that GCV can be administered in combination with these other drugs for treatment of various opportunistic infections in AIDS patients without compromising the efficacy of GCV against CMV.
Freitas
V R
VR
Syntex Research, Palo Alto, CA 94304.
Fraser-Smith
E B
EB
Matthews
T R
TR
D000666:Amphotericin B / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000633:toxicity; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000633:toxicity; D002478:Cells, Cultured; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D003622:Dapsone / Q000627:therapeutic use / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage* / Q000633:toxicity; D006801:Humans; D007654:Ketoconazole / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D013045:Species Specificity; D013420:Sulfamethoxazole / Q000627:therapeutic use / Q000633:toxicity; D016019:Survival Analysis; D014295:Trimethoprim / Q000627:therapeutic use / Q000633:toxicity; D010948:Viral Plaque Assay
D000935:Antifungal Agents; D000998:Antiviral Agents; D000666:Amphotericin B; D003622:Dapsone; D014295:Trimethoprim; D013420:Sulfamethoxazole; D015774:Ganciclovir; D007654:Ketoconazole