Evaluation of the toxicity and antiviral activity of carbocyclic 3-deazaadenosine against respiratory syncytial and parainfluenza type 3 viruses in tissue culture and in cotton rats.
The toxicity and antiviral efficacy of carbocyclic 3-deazaadenosine (Cc3Ado) against respiratory syncytial (RSV) and parainfluenza type 3 (PIV3) virus infections were tested in tissue culture and in cotton rats. The mean median efficacious dose (ED50) of Cc3Ado in HEp2 cells against RSV and PIV3 was 9 and 14 micrograms/ml, respectively. These values were 85- and 55-fold less than the median inhibitory (toxic) dose (ID50) of Cc3Ado in this cell line (750 micrograms/ml), and similar to values obtained for ribavirin. Cc3Ado exhibited no significant antiviral activity against influenza A, influenza B, adeno type 5 or adeno type 7 viruses (all ED50 were greater than 1000 micrograms/ml). In cotton rats, animals given greater than or equal to 1 mg/kg/day Cc3Ado intraperitoneally on days 1, 2 and 3 after experimental challenge with virus, consistently had significant reductions in pulmonary RSV and PIV3 titers compared to pulmonary virus titers in comparably treated control animals. The minimum efficacious dose of ribavirin given under the same conditions was 30 mg/kg/day. Cc3Ado was also efficacious in cotton rats when given orally by gavage, or when different administration schedules were used. The median efficacious dose of Cc3Ado when given orally was 10 mg/kg/day. No significant toxic effects were noted in cotton rats, even in animals given 20 mg/kg daily for eight consecutive days.
Wyde
P R
PR
Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030.
Ambrose
M W
MW
Meyer
H L
HL
Zolinski
C L
CL
Gilbert
B E
BE
D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008297:Male; D010224:Parainfluenza Virus 3, Human / Q000187:drug effects* / Q000254:growth & development; D018184:Paramyxoviridae Infections / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000254:growth & development; D010253:Respirovirus Infections / Q000188:drug therapy / Q000473:pathology; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; C034072:carbocyclic 3-deazaadenosine; D014372:Tubercidin