Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 521, Issue 1-3, Pages 86-94Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2005.08.016
Keywords
(+)-methamphetamine; (+)-amphetamine; monoclonal antibody; (rat)
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Funding
- NIDA NIH HHS [DA11560, DA14361, F31 DA05939] Funding Source: Medline
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The roles of monoclonal antibody affinity and treatment time of (+)-methamphetamine-induced pharmacological effects in rats were studied using two anti-(+)-methamphetamine monoclonal antibodies. These studies tested the preclinical protective effects of monoclonal antibody antagonists in (+)-methamphetamine overdose and pretreatment scenarios. The higher affinity antibody (mAb6H4; K-D = 11 nM for (+)-methamphetamine) more effectively antagonized (+)-methamphetamine-induced behavioral effects (distance and rearing) than the low affinity antibody (designated mAb6HS; K-D = 250 nM) and had a longer duration of action. Both antibodies more effectively reduced (+)methamphetamine effects in the overdose model than in the pretreatment model. (+)-Methamphetamine pharmacokinetic studies showed the mAb6H4 significantly reduced brain concentrations over time in both models. However, while mAb6H4 immediately reduced brain concentrations in the overdose model, it did not prevent the initial distribution of (+)-methamphetamine into the brain in the pretreatment model. Thus, anti-(+)-methamphetamine monoclonal antibody affinity and administration time (relative to (+)-methamphetamine dosing) are critical determinants of therapeutic success. (c) 2005 Elsevier B.V. All rights reserved.
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