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.
|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|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be