Effects of a superantigen-antibody recombinant fusion protein (r-C242 Fab-SEA) on toxicological responses in the anaesthetised rabbit.
The objective was to study toxin-induced effects on physiological parameters in the rabbit and whether these parameters show dose-response and co-variation after administration of a recombinant fusion protein between staphylococcal enterotoxin (SE) and the Fab fragment of an antibody. Rabbits are very sensitive to SE toxins and the cardiovascular and immune effects are similar to those observed in septic shock in man. The test compound, r-C242 Fab-SEA, was administered intravenously to anaesthetised New Zealand white rabbits at doses in the range of 0.00005-50 microg/kg. All rabbits were checked for titres of anti-SEA antibodies before entering the experiment, since they could neutralise the effect of the test compound. Heart rate, blood pressure and body temperature were continuously monitored before and during 6 h after dosing. Immediately before the start of administration and 3 and 6 h during the experiment, blood gases (pO(2) and pCO(2)), pH, haematology, clinical chemistry, cytokine response (TNF-alpha) and trace elements (Mn, Cu, Zn, Se, Ag, Cd, Hg and Pb) were measured. No mortality occurred, but at 50 microg/kg severe adverse clinical signs developed. The decrease in blood pressure was weakly dose-related. Heart rate, ECG, body temperature, pCO(2) and pH were not affected by the treatment. pO(2) tended to increase as a function of time, but not in relation to dose. WBC and PLT decreased dose dependently. TNF-alpha was not affected by the treatment. The major effects on clinical chemistry were a dose-dependent increase in AST and creatinine. Potassium and urea showed dose dependent increases, mainly at higher doses, though these changes were of less value for drug selection purposes. Trace element changes were observed, including an increase in Mn and a decrease of Zn at all doses. The Cu/Zn ratio decreased below normal at low doses, whereas at high doses in which adverse effects developed, it increased above normal. Post mortem examination revealed minimal to moderate dose-related granulocytic infiltrate in the lungs. The present study showed dose-response and co-variation between several changes in cardiovascular, haematology, clinical chemistry and trace element parameters during the initial phase of toxin-induced effects preceding a possible lethal endpoint and associated patho-physiological changes.
Ilbäck
Nils Gunnar
NG
Division of Toxicology, National Food Administration, Uppsala, Sweden. ngil@slv.se
Gunnarsson
Kjell
K
Persson
Robert
R
Lindh
Ulf
U
Stålhandske
Torbjörn
T
D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects / Q000503:physiopathology; D019963:Clinical Chemistry Tests; D004305:Dose-Response Relationship, Drug; D004768:Enterotoxins / Q000008:administration & dosage / Q000633:toxicity*; D006098:Granulocytes / Q000187:drug effects / Q000473:pathology; D006403:Hematologic Tests; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000633:toxicity*; D007275:Injections, Intravenous; D008136:Longevity / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D011817:Rabbits; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000633:toxicity*; D013210:Staphylococcus / Q000276:immunology; D018089:Superantigens / Q000633:toxicity; D018675:Toxicity Tests
D004768:Enterotoxins; D007140:Immunoglobulin Fab Fragments; D011993:Recombinant Fusion Proteins; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal