A catalytic antibody against cocaine attenuates cocaine's cardiovascular effects in mice: a dose and time course analysis.
The murine monoclonal antibody 15A10 (mAb 15A10), elicited by a transition-state analog for cocaine hydrolysis, has previously been shown to metabolize cocaine in vitro and in vivo. The present experiments were designed to evaluate further the in vivo effectiveness of mAb 15A10 in blocking cardiovascular effects of acute cocaine administration. Balb/c mice were implanted with a femoral artery catheter utilized for mean arterial pressure (MAP) monitoring, and administered intravenous (i.v.) pretreatments of either mAb 15A10 (10, 32, 100 and 300 mg/kg) or vehicle prior to cocaine injection (100 mg/kg, i.p.). A time course analysis for mAb 15A10's effect was also conducted, for which either vehicle or 100 mg/kg mAb 15A10 was infused 1, 3, 10 and 30 days prior to cocaine treatment. During the cardiovascular recording sessions, mice were awake and freely moving within a limited area. Increases in MAP (approximately 25 mm Hg) following cocaine injection were dose-dependently attenuated by mAb 15A10. The antibody-attenuated cocaine-induced increases in MAP at 1- and 3-day pretreatment times, and reduced mortality at some of the time points studied. With 100 mg/kg antibody, plasma cocaine levels were significantly decreased early in the recording session, whereas levels of ecgonine methyl ester increased significantly. Although 10-fold greater quantities of antibody are required to observe significant effects in mouse, compared to our previous studies in rats, the present mouse model provides a convenient paradigm for investigating catalytic and non-catalytic antibodies.
Briscoe
R J
RJ
Central Research Division, Pfizer, Inc. Eastern Point Road, Groton, CT 06340, USA.
Jeanville
P M
PM
Cabrera
C
C
Baird
T J
TJ
Woods
J H
JH
Landry
D W
DW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003042:Cocaine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013997:Time Factors
D000911:Antibodies, Monoclonal; D007202:Indicators and Reagents; C005617:ecgonine; D003042:Cocaine