ABSTRACT
Recombinant (r) human (hu) manganese (Mn) and copper-zinc (CuZn) superoxide dismutase (SOD) were evaluated for their cytotoxicity and antiviral activity against respiratory syncytial virus (RSV) in tissue culture and in cotton rats. No apparent cytotoxicity or inhibition of RSV was observed in the tissue culture studies (both compounds had IC50 and EC50 values > or = 1000 micrograms/ml and a selective index = 1). However, significant reductions in mean pulmonary RSV titers (ranging between 0.5 and 1.9 log10/g of lung compared with the mean pulmonary viral titers detected in similarly inoculated, placebo-treated control animals) were seen in most of the experiments, in which experimentally infected cotton rats were exposed to continuous small-particle aerosols (reservoir concentrations > or = 20 mg/ml) containing either rhuMnSOD or rhuCuZnSOD. This protective effect was dose dependent and not observed when either rSOD compound was administered parenterally (intraperitoneally) or intranasally. No toxic effects were noted in any of the cotton rats exposed to aerosols of either rhuMn or CuZnSOD; nor was any evidence of drug-induced histopathology observed in sections of lung prepared from these animals.
Subject(s)
Antiviral Agents/pharmacology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Viruses/drug effects , Superoxide Dismutase/pharmacology , Aerosols , Animals , Antiviral Agents/metabolism , Antiviral Agents/toxicity , Chlorocebus aethiops , Copper , Dose-Response Relationship, Drug , Humans , Lung/metabolism , Manganese , Recombinant Fusion Proteins/genetics , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Virus Infections/virology , Sigmodontinae , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Superoxide Dismutase/toxicity , Tumor Cells, Cultured , Vero Cells , ZincABSTRACT
N-(phosphonoacetyl)-L-aspartate (PALA), a potent inhibitor of L-aspartic acid transcarbamoylase, was evaluated for cytotoxicity and antiviral activity against three different paramyxoviruses in tissue culture, and for antiviral efficacy and toxicity in vivo using a cotton rat-respiratory syncytial virus (RSV) model. Significant in vitro cytotoxicity was observed in proliferating cultures of HEp-2 (IC50 = 250 micrograms/ml) and Vero cells (IC50 = 32 micrograms/ml), but was less evident in cultures containing confluent monolayers (i.e., stationary cells) of these cells, or in cultures of Madin Darby canine kidney (MDCK) cells (these IC50 values were all > or = 750 micrograms/ml, with 1000 micrograms/ml being the maximum concentration tested). Mean selective indices (ratio of the median cytotoxic dose: median efficacious dose) of 1, 72 and 146 were obtained against parainfluenza virus type 3, RSV and measles virus, respectively, when PALA was tested against these viruses using confluent HEp-2 and Vero cell monolayers. In cotton rats, significant reductions in pulmonary titers (0.8-1.4 log10/g lung) compared to pulmonary viral titers in placebo-treated control animals, were consistently seen in cotton rats given > or = 10 mg of PALA/kg/day (b.i.d.) intraperitoneally on days 1-3 postinfection with either subtype A or B RSV. No toxic effects were noted even in animals given 100 mg of PALA/kg/day for 7 consecutive days.
