title: Effects of four antiviral substances on lethal vaccinia virus (IHD strain) respiratory infections in mice.
abstract: Intranasal infection of BALB/c mice with the IHD strain of vaccinia virus was found to cause pneumonia, profound weight loss and death. Cidofovir, hexadecyloxypropyl-cidofovir (HDP-CDV), the diacetate ester prodrug of 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (HOE961), and ribavirin were used to treat the infections starting 24h after virus exposure. Single intraperitoneal (i.p.) cidofovir treatments of 100 and 30 mg/kg led to 90-100% survival compared with no survivors in the placebo group, whereas a 10 mg/kg dose was ineffective. The 100 mg/kg treatment reduced lung and snout virus titres on day 3 of the infection by 20- and 8-fold, respectively. Mean arterial oxygen saturation levels in these two cidofovir treatment groups were significantly higher than placebo on days 4 through 6 of the infection, indicating an improvement in lung function. Effects of cidofovir on viral pathogenesis were studied on days 1, 3 and 5 of the infection, and demonstrated statistically significant reductions in lung consolidation scores, lung weights, lung virus titre and snout virus titres on days 3 and 5. Cidofovir treatment also reduced virus titres in other tissues and body fluid, including blood, brain, heart, liver, salivary gland and spleen. HDP-CDV was given by oral gavage at 100, 50 and 25mg/kg doses one time only, resulting in 80-100% survival. Lower daily oral doses of 10 and 5mg/kg per day given for 5 days protected only 30% of animals from death. Oral doses (100, 50 and 25 mg/kg per day) of HOE961 for 5 days protected all animals, whereas equivalent oral doses of ribavirin were completely ineffective. The rapidity of recovery from weight loss during the infection was a function of dose of compound administered. These data indicate the utility of parenteral cidofovir, oral HDP-CDV and oral HOE961 in treating severe respiratory infections caused by this virus.
authors.affiliation: Department of Animal, Dairy and Veterinary Sciences, Institute for Antiviral Research, Utah State University, Logan, UT 84322-5600, USA. dsmee@cc.usu.edu
authors.forename: Donald F
authors.initials: DF
authors.lastname: Smee
authors.forename: Min-Hui
authors.initials: MH
authors.lastname: Wong
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Bailey
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sidwell
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D001835:Body Weight; D001921:Brain / Q000821:virology; D000077404:Cidofovir; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D006321:Heart / Q000821:virology; D008099:Liver / Q000821:virology; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use; D010100:Oxygen / Q000097:blood; D011687:Purines / Q000008:administration & dosage / Q000627:therapeutic use; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000821:virology*; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use; D012469:Salivary Glands / Q000821:virology; D013154:Spleen / Q000821:virology; D016896:Treatment Outcome; D014615:Vaccinia / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D014616:Vaccinia virus / Q000302:isolation & purification; D010948:Viral Plaque Assay; D014766:Viremia
chemical_list: D000998:Antiviral Agents; C096889:HOE 961; D063065:Organophosphonates; D011687:Purines; D012254:Ribavirin; D003596:Cytosine; D000077404:Cidofovir; D010100:Oxygen