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| Quantitation of human immunodeficiency virus (HIV) surrogate and tenofovir distribution in the gastrointestinal and female genital tracts | |
| Louissaint, Nicolette Alexandrea | |
| 出版年 | 2010 |
| 学位类型 | 博士 |
| 导师 | Hendrix, Craig W. |
| 学位授予单位 | The Johns Hopkins University |
| 英文摘要 | Drugs for pre-exposure prophylaxis (PrEP) of HIV infection are being developed as an adjunctive measure to prevent sexual HIV transmission. HIV transmission and drug distribution in both female genital (FGT) and gastrointestinal (GI) tracts must be considered during development, as both vaginal and anal intercourse are critical for transmission. The goal of this dissertation was to determine the distribution of viral surrogates and an anti-HIV drug in the GI and FGT. The distribution of radiolabeled HIV surrogates in areas exposed to HIV after sex was quantified in the distal colon (four men) and the female genital tract (seven women). Both studies used noninvasive imaging and direct mucosal sampling to examine the distribution of radiolabeled HIV surrogates in the lumen and tissues of these compartments. Single-photon emission computed tomography/computed tomography analysis of radiotracer distribution revealed that the surrogates distributed similarly. In the GI, the highest concentration of radioactivity was in the rectosigmoid colon. In the FGT it was the pericervical region. In all tissue biopsies, less than 2% of CD4 cells were radiolabeled. Tenofovir (TFV) was studied first in a single dose study and in a steady-state study in HIV-infected patients, to describe distribution of the drug and its active moiety, tenofovir diphosphate (TFV-DP). In the single dose study, blood and peripheral blood mononuclear cells (PBMCs) were collected post-dosing and analyzed for drug. Data analysis reveals a Cmax of 60.527 ng/mL TFV at 2.24 h, and biphasic decay. Intracellular TFV-DP has a Cmax of 20.07 and 19.47 fmol/106 cells for the subjects. In the steady-state study, cell subsets from mucosal tissue and blood were isolated to analyze TFV-DP from HIV-positive subjects on regimens that included TDF. The median TFV-DP concentration were 143.7 fmol/106 epithelial cells, 572.0 fmol/106 CD4 T-helper cells, and 223.5 fmol/106 monocyte/macrophages. In blood, the median TFV-DP concentrations were 26.3 fmol/106 CD4 T-helper cells and 41.2 fmol/106 monocyte/macrophages. In summary, this work developed methods to quantify HIV surrogate and drug distribution and clearance in sexually receptive tissue compartments. Combining these methods can advance more thoughtfully by designing a drug to outdistance and outlast HIV in the sites of sexual transmission. |
| 英文关键词 | Antiretrovirals Gastrointestinal tract Genital tracts HIV Microbicides Tenofovir |
| 语种 | 英语 |
| 国家 | United States |
| 来源学科分类 | Pharmacology |
| URL | https://pqdtopen.proquest.com/doc/375479825.html?FMT=AI |
| 来源机构 | Johns Hopkins University |
| 资源类型 | 学位论文 |
| 条目标识符 | http://119.78.100.177/qdio/handle/2XILL650/244435 |
| 推荐引用方式 GB/T 7714 | Louissaint, Nicolette Alexandrea. Quantitation of human immunodeficiency virus (HIV) surrogate and tenofovir distribution in the gastrointestinal and female genital tracts[D]. The Johns Hopkins University,2010. |
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