An integrated methodological approach for the study of the transplacental transfer of glyburide: From the subcellular to the clinical perspective
Bibliographic record
Abstract
Gestational diabetes, left untreated, can result in severe fetal consequences. Glyburide, a drug used to treat gestational diabetes, has been shown, to be actively effluxed out of the placenta in the fetal to maternal direction. ABC-transporters such as P-glycoprotein (PGP), breast Cancer resistant protein (BCRP) and the multi drug resistance proteins (MRP 1, 2 and 3) are expressed in the human placenta and may be involved in the transport of drugs from the fetus to the mother. The objective of the present thesis is to (1) determine which placental ABC efflux transporter(s) are involved in the active transport of glyburide in the human placenta and (2) to establish an integrative approach to investigating the transplacental behaviour of drugs in pregnancy. At the cellular level, functional studies in ABC transporter over-expressing cell lines were performed in the presence and absence of specific inhibitors. Cellular uptake studies have shown that glyburide is likely transported by BCRP and MRP3. Subsequently, the transport of glyburide in the presence of MRP inhibitor indomethacin was investigated in the dually perfused human placenta model. At the organ level, there was no significant difference in the rate of transfer of glyburide in the presence or absence of the MRP inhibitor indomethacin. At the subcellular level, 3H-glyburide efflux was measured in the presence and absence of specific ABC transporter inhibitors in purified placental brush border membrane vesicles. Vesicular uptake studies in the human placenta indicate that glyburide is likely transported by placental BCRP and not MRP 1, 2, or 3. Glyburide's efflux from the human placenta, poise this drug as a potential model for the design of pregnancy specific drugs. Furthermore, in the advent of their creation, an ethical analysis of performing clinical trials in women undergoing pregnancy termination is considered as a potential population for the study of drugs designed particularly for pregnancy. The presented integrative approach can be easily adopted clinically and would not only generate the information necessary to eliminate the dearth of data that exist regarding drug use in pregnancy but ultimately improve the therapeutic treatment of pregnant women and their unborn fetus.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".