Dissertation/Thesis Abstract

Development of a pregnant rat model for treating methamphetamine abuse with monoclonal antibodies
by White, Sarah J., Ph.D., University of Arkansas for Medical Sciences, 2008, 196; 3340147
Abstract (Summary)

The first set of studies hypothesized that chronic maternal administration of (+)-methamphetamine (METH; 5.6-17.8 mg/kg/day) from gestational day 7 (GD7; before organogenesis) to GD21 (1-2 days antepartum) results in dose- and gestational time-dependent effects in pregnant rats and litters. METH dose- and gestational time-dependent health and behavioral effects were found in the pregnant rats, whereby rats either recovered from METH-induced effects by mid-gestation or died. Litters of the surviving dams were similar in litter size and weight to controls by GD21. Late-gestational stage reductions in METH systemic clearance were found in the dams, which were dose-independent. Although the maternal and fetal serum concentrations of METH and its metabolite (+)-amphetamine (AMP) were similar, METH and AMP fetal brain concentrations were three-fold lower.

The second set of studies hypothesized that acute METH dosing during early- and late-stage pregnancy causes dose- and gestational time-dependent METH and AMP pharmacokinetics. Timed-pregnant rats received either 1 mg/kg iv METH on GD7 or 1, 3 or 5.6 mg/kg iv METH on GD21. The results showed gestational time-dependent reductions in clearance between GD7 and GD21 but dose-independent pharmacokinetics on GD21.

The final studies hypothesized that high-affinity anti-METH/AMP monoclonal antibody (mAb) protects pregnant rats and litters from adverse effects by redistributing METH and AMP from their brains. Pregnant rats received 1 mg/kg iv METH on GD21, followed 30 min later by administration of vehicle or anti-METH/AMP mAb. MAb-treated maternal serum METH and AMP concentrations remained substantially elevated due to a >400% rise in METH and AMP serum protein binding. Fetal serum METH and AMP protein binding also increased, but fetal serum METH and AMP concentrations were lower. Maternal and fetal brain METH and AMP concentrations were also lower after mAb treatment, but returned to control levels by 5 h.

In conclusion, METH and AMP maternal pharmacokinetics were altered during late-stage pregnancy in chronically and acutely dosed rats, suggesting enhanced vulnerability before delivery. Anti-METH/AMP mAb offered acute protection by reducing maternal and fetal brain METH and AMP concentrations during peak exposure. These studies show promise for maternal and fetal protection from METH and AMP exposure by treatment with anti-METH/AMP mAb.

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, Fetal protection, Methamphetamine, Monoclonal antibodies, Pregnant
Publication Number: 3340147
ISBN: 978-0-549-94390-7
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