Dissertation/Thesis Abstract

Monoclonal antibodies as protective medications for drug abuse during pregnancy
by Hubbard, Jonathan J., Ph.D., University of Arkansas for Medical Sciences, 2008, 201; 3340141
Abstract (Summary)

The overall hypothesis for this research is that drug-specific monoclonal antibodies (mAb) can protect the maternal-fetal unit from adverse drug-induced effects. Experiments investigating this hypothesis studied IgG1 mAb pharmacological function in pregnant rats from gestation day (GD) 8 to postpartum day (PPD) 20. In the first studies, groups of pregnant rats (n=4) received an iv-bolus dose of anti-phencyclidine (PCP) mAb6B5 along with a [3H]-mAb tracer on GD8, GD15, and PPD1, using nulliparous female (NPF) controls. Pharmacokinetic (PCKN) analysis of mAb6B5 serum concentration-time data found that, while mAb t1/2λz did not differ between NPF controls, mAb t1/2λz significantly (p<0.05) changed in a gestation stage-dependent manner during and immediately following pregnancy. Additional experiments and analyses found dose- and mAb-independent changes in mAb clearance and volume of distribution underlying these t1/2λz changes.

The second set of studies analyzed these mAb PCKN changes in conjunction with maternal health data and discovered a temporal correlation between the initiation of both 3rd trimester mAb PCKN changes and accelerated maternal weight gain. Translational integration of these findings used maternal weight as a surrogate for the start of mAb PCKN changes to design an adaptive mAb dosing regimen, which maintained mAb6B5 steady-state throughout pregnancy.

In the third set of studies, this mAb6B5 treatment protocol protected PCP-infused pregnant rats by substantially lowering maternal brain PCP levels vs. vehicle-treated controls (p<0.05) throughout pregnancy. In fetuses, PCP levels were increased on GD9 but decreased after GD15 in mAb6B5-treated dams vs. controls (p<0.05). In a model of acute PCP abuse, this same mAb6B5 treatment protocol did not significantly alter PCP-induced cardiovascular stimulation but slightly alleviated some PCP-induced locomotor effects (p<0.05). Importantly, repeated mAb6B5 treatment in these animals significantly decreased the incidence of in utero fetal demise vs. vehicle-treated controls (p=0.008; odds ratio=3.2).

The studies described here show that mAb pharmacological function changes during rat pregnancy, that an adaptive mAb-dosing strategy can successfully maintain mAb steady-state during pregnancy, and that mAb6B5 dosed accordingly can protect mother and fetus from PCP-induced adverse health effects, including fetal death. These novel findings represent important contributions to understanding mAb pharmacological function during rat pregnancy.

Indexing (document details)
Advisor: Owens, S. Michael
School: University of Arkansas for Medical Sciences
School Location: United States -- Arkansas
Source: DAI-B 69/12, Dissertation Abstracts International
Subjects: Medicine, Pharmacology, Immunology
Keywords: Drug abuse, Monoclonal antibodies, Phencyclidine, Pregnancy
Publication Number: 3340141
ISBN: 978-0-549-94384-6
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