Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)-cytosine and 9-(1,3-dihydroxy-2-propoxymethyl)-guanine in the treatment of intracerebral murine cytomegalovirus infections in immunocompetent and immunodeficient mice.
The efficacy of HPMPC and DHPG against systemic and intracerebral murine cytomegalovirus (MCMV) infections was examined in immunocompetent NMRI mice and in mice with severe combined immunodeficiency (SCID). HPMPC proved to be far superior to DHPG in preventing mortality and growth retardation in MCMV-infected NMRI mice even when given as a single dose on the day of infection. In intraperitoneally infected SCID mice, HPMPC administered as a single dose of 2, 10, 20 or 50 mg/kg per week increased the survival period of the mice by 22, 49, 77 and 156 days, respectively. In contrast, DHPG at daily doses of 10, 20 or 50 mg/kg for five consecutive days every week did not delay death by more than 13, 17 and 21 days, respectively. About one week before the MCMV-infected SCID mice (treated with either DHPG or HPMPC) died, they developed signs of neurological disease and intranuclear inclusion-bearing cells were found in their brains. The virus that was recovered from the brains of these mice did not prove to be resistant to HPMPC or DHPG. Only the virus recovered from the brains of mice treated with HPMPC at a dosage of 50 mg/kg/week had a slightly decreased susceptibility to HPMPC. When HPMPC (50 mg/kg for 4 consecutive days) was administered to SCID mice at the time when neurological symptoms became apparent, death of the animals could be delayed by another 35 to 40 days.
Neyts
J
J
Rega Institute for Medical Research, Leuven Catholic University, Belgium.
Sobis
H
H
Snoeck
R
R
Vandeputte
M
M
De Clercq
E
E
D000818:Animals; D000831:Animals, Newborn; D000998:Antiviral Agents / Q000627:therapeutic use*; D001921:Brain / Q000382:microbiology / Q000473:pathology; D001927:Brain Diseases / Q000188:drug therapy*; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D015774:Ganciclovir / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000627:therapeutic use*
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir; D015774:Ganciclovir