Oral treatment of murine cytomegalovirus infections with ether lipid esters of cidofovir.

Abstract

To improve the oral bioavailability of cidofovir (CDV), a series of ether lipid ester prodrugs were synthesized and evaluated for activity against murine cytomegalovirus (MCMV) infection. Four of these analogs, hexadecyloxypropyl (HDP)-CDV, octadecyloxyethyl (ODE)-CDV, oleyloxyethyl (OLE)-CDV, and oleyloxypropyl (OLP)-CDV, were found to have greater activity than CDV against human CMV and MCMV in vitro. The efficacy of oral treatment with these compounds against MCMV infections in BALB/c mice was then determined. Treatment with HDP-CDV, ODE-CDV, OLE-CDV, or OLP-CDV at 2.0 to 6.7 mg/kg of body weight provided significant protection when daily treatments were initiated 24 to 48 h after viral inoculation. Additionally, HDP-CDV or ODE-CDV administered twice weekly or as a single dose of 1.25 to 10 mg/kg was effective in reducing mortality when treatment was initiated at 24 h, 48 h, or, in some cases, 72 h after viral inoculation. In animals treated daily with HDP-CDV or ODE-CDV, virus titers in lung, liver, spleen, kidney, pancreas, salivary gland, and blood were reduced 3 to 5 log(10)-fold, which was comparable to CDV given intraperitoneally. These results indicated that HDP-CDV or ODE-CDV given orally was as effective as parenteral CDV for the treatment of experimental MCMV infection and suggest that further evaluation for use in CMV infections in humans is warranted.

• Authors: Earl R Kern, Deborah J Collins, W Brad Wan, James R Beadle, Karl Y Hostetler, Debra C Quenelle
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 48 Issue 9 Pg. 3516-22 (Sep 2004) ISSN: 0066-4804 [Print] United States
• PMID: 15328119 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antiviral Agents
• Esters
• Lipids
• Organophosphonates
• Organophosphorus Compounds
• Cytosine
• Cidofovir

Topics

• Animals
• Antiviral Agents (pharmacokinetics, therapeutic use)
• Cidofovir
• Cytomegalovirus (drug effects)
• Cytomegalovirus Infections (drug therapy, virology)
• Cytosine (analogs & derivatives, pharmacokinetics, therapeutic use)
• Esters (chemical synthesis, therapeutic use)
• Female
• Injections, Intraperitoneal
• Injections, Intravenous
• Lipids (chemistry)
• Mice
• Mice, Inbred BALB C
• Organophosphonates
• Organophosphorus Compounds (pharmacokinetics, therapeutic use)
• Structure-Activity Relationship
• Viral Load