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| Monoclonal antibodies as protective medications for drug abuse during pregnancy | |
| Hubbard, Jonathan J. | |
| 出版年 | 2008 |
| 学位类型 | 博士 |
| 导师 | Owens, S. Michael |
| 学位授予单位 | University of Arkansas for Medical Sciences |
| 英文摘要 | 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. |
| 英文关键词 | Drug abuse Monoclonal antibodies Phencyclidine Pregnancy |
| 语种 | 英语 |
| 国家 | United States |
| 来源学科分类 | Medicine; Pharmacology; Immunology |
| URL | https://pqdtopen.proquest.com/doc/304410921.html?FMT=AI |
| 来源机构 | University of Arkansas for Medical Sciences |
| 资源类型 | 学位论文 |
| 条目标识符 | http://119.78.100.177/qdio/handle/2XILL650/244226 |
| 推荐引用方式 GB/T 7714 | Hubbard, Jonathan J.. Monoclonal antibodies as protective medications for drug abuse during pregnancy[D]. University of Arkansas for Medical Sciences,2008. |
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