Byrnes-Blake Kelly A, Laurenzana Elizabeth M, Landes Reid D, Gentry W Brooks, Owens S Michael
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Eur J Pharmacol. 2005 Oct 3;521(1-3):86-94. doi: 10.1016/j.ejphar.2005.08.016. Epub 2005 Sep 21.
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; KD=11 nM for (+)-methamphetamine) more effectively antagonized (+)-methamphetamine-induced behavioral effects (distance and rearing) than the low affinity antibody (designated mAb6H8; KD=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.
使用两种抗（+）-甲基苯丙胺单克隆抗体研究了单克隆抗体亲和力和治疗时间对（+）-甲基苯丙胺诱导的大鼠药理作用的影响。这些研究测试了单克隆抗体拮抗剂在（+）-甲基苯丙胺过量和预处理情况下的临床前保护作用。高亲和力抗体（mAb6H4；对（+）-甲基苯丙胺的KD = 11 nM）比低亲和力抗体（命名为mAb6H8；KD = 250 nM）更有效地拮抗（+）-甲基苯丙胺诱导的行为效应（距离和竖毛），并且作用持续时间更长。在过量模型中，两种抗体比预处理模型更有效地降低（+）-甲基苯丙胺的作用。（+）-甲基苯丙胺药代动力学研究表明，在两种模型中，mAb6H4均随时间显著降低脑浓度。然而，虽然mAb6H4在过量模型中立即降低了脑浓度，但在预处理模型中它并未阻止（+）-甲基苯丙胺最初分布到脑中。因此，抗（+）-甲基苯丙胺单克隆抗体的亲和力和给药时间（相对于（+）-甲基苯丙胺给药）是治疗成功的关键决定因素。
