Pulsatility index in combination with biomarkers or mean arterial pressure for the prediction of pre-eclampsia: Systematic literature review and meta-analysis

<div><p><i>Introduction.</i> Our objective was to perform a meta-analysis examining the sensitivity of pulsatility index (PI) and various biomarkers and PI and mean arterial pressure (MAP) for the prediction of pre-eclampsia.</p><p><i>Material and methods.</i> PubMed, CENTRAL, and Embase databases were searched from inception until 8 May 2014 using combinations of the search terms: pre-eclampsia, ultrasonography, pregnancy, biomarker, mean arterial pressure, placental protein 13, pregnancy-associated plasma protein-A, placental growth factor, activin A, inhibin A, pulsatility index. The pooled sensitivity of PI + biomarkers and PI + MAP were calculated, and reported with corresponding 95% confidence intervals (CIs).</p><p><i>Results.</i> Fifteen studies were included in the meta-analysis. The pooled sensitivity of all biomarkers for the prediction of pre-eclampsia was 0.669 (95% CI 0.610–0.723), for the prediction of early-onset pre-eclampsia was 0.830 (95% CI 0.794–0.861), and for the prediction of late-onset pre-eclampsia was 0.564 (95% CI 0.499–0.627). Similarly, the predictive ability of PI + MAP for early-onset pre-eclampsia was good (sensitivity 0.894), while that for late-onset was poor (sensitivity 0.570).</p><p><i>Conclusion.</i> The combination of PI and different biomarkers or MAP exhibits a good predictive ability for early-onset pre-eclampsia, and poor predictive ability for late-onset pre-eclampsia.</p></div

Stereoselective Regulation of P-gp Activity by Clausenamide Enantiomers in Caco-2, KB/KBv and Brain Microvessel Endothelial Cells

<div><p>The (−)- and (+)-clausenamide (CLA) enantiomers have different pharmacokinetic effects in animals, but their association with putative stereoselective regulation of P-glycoprotein (P-gp) remains unclear. Using three cells expressing P-gp—Caco-2, KBv and rat brain microvessel endothelial cells(RBMEC), this study investigated the association of CLA enantiomers with P-gp. The results showed that the rhodamine 123 (Rh123) accumulation, an indicator of P-gp activity, in Caco-2, KBv and RBMECs was increased by (−)CLA (1 or 5 μmol/L) at 8.2%–28.5%, but reduced by (+)CLA at 11.7%–25.9%, showing stereoselectivity in their regulation of P-gp activity. Following co-treatment of these cells with each CLA enantiomer and verapamil as a P-gp inhibitor, the (+)-isomer clearly antagonized the inhibitory effects of verapamil on P-gp efflux, whereas the (−)-isomer had slightly synergistic or additive effects. When higher concentrations (5 or 10 μmol/L) of CLA enantiomers were added, the stimulatory effects of the (+)-isomer were converted into inhibitory ones, leading to an enhanced intracellular uptake of Rh123 by 24.5%–58.2%; but (−)-isomer kept its inhibition to P-gp activity, causing 30.0%–63.0% increase in the Rh123 uptake. The biphasic effects of (+)CLA were confirmed by CLA uptake in the Caco-2 cells. (+)CLA at 1 μmol/L had significantly lower intracellular uptake than (−)CLA with a ratio[(−)/(+)] of 2.593, which was decreased to 2.167 and 1.893 after CLA concentrations increased to 2.5 and 5 μmol/L. Besides, in the non-induced KB cells, (+)CLA(5 μmol/L) upregulated P-gp expression at 54.5% relative to vehicle control, and decreased Rh123 accumulation by 28.2%, while (−)CLA(5 μmol/L) downregulated P-gp expression at 15.9% and increased Rh123 accumulation by 18.0%. These results suggested that (−)CLA could be a P-gp inhibitor and (+)CLA could be a modulator with concentration-dependent biphasic effects on P-gp activity, which may result in drug—drug interactions when combined with other P-gp substrate drugs.</p></div

Chromatograms of clausenamide(CLA) and glipizide(IS) with retention time of 2.70 and 3.02min(A), and intracellular concentrations in Caco-2 cells treated with (-) or (+)CLA(B).

<p>Data were presented as Mean±SD from 3 independent experiments. (-) or (+)CLA: 1, 2.5 and 5 μmol/L; *<i>P</i><0.05,**<i>P</i><0.01 <i>vs</i>. (-)CLA.</p

Effects of clausenamide(CLA) enantiomers on the P-gp expression(A) and the accumulation of rhodamine 123(B) in KB cells.

<p>Data were presented as Mean±SD from 3–5 independent experiments; (-) or (+)CLA: 1, or 5, or 10 μmol/L; verapamil(Ver): 100 μmol/L; rhodamine123: 5 μmol/L; *<i>P</i><0.05, **<i>P</i><0.01 <i>vs</i>. Control; ^#<i>P</i><0.05, ^##<i>P</i><0.01 <i>vs</i>. (-)CLA 5μmol/L; ^&<i>P</i><0.05 <i>vs</i>. (-)CLA 5μmol/L; ^@@<i>P</i><0.01 <i>vs</i>. (+)CLA 5μmol/L.</p

Effects of clausenamide(CLA) enantiomers at different concentrations on the accumulation of rhodamine 123 in the absence(A) or presence(B) of P-gp inhibitor verapamil in KBv cells.

<p>Data were presented as Mean±SD from 4–5 independent experiments; (-) or (+)CLA: 5 μmol/L or 10 μmol/L; verapamil: 200 μmol/L; rhodamine123: 5 μmol/L; *<i>P</i><0.05, **<i>P</i><0.01 <i>vs</i>. Control; ^##<i>P</i><0.01 <i>vs</i>. (-)CLA 5 μmol/L; ^&<i>P</i><0.05 <i>vs</i>. (-)CLA 5 μmol/L; ^@@<i>P</i><0.01 <i>vs</i>. (+)CLA 5 μmol/L.</p

Effects of clausenamide(CLA) enantiomers at different concentrations on the accumulation of rhodamine 123 in the absence(A) or presence(B) of P-gp inhibitor verapamil in Caco-2 cells.

<p>Data were presented as Mean±SD from 6 independent experiments; (-) or (+)CLA: 1 or 5 μmol/L; verapamil: 200 μmol/L; rhodamine123: 5 μmol/L; **<i>P</i><0.01 <i>vs</i>. Control or Verapamil; ^##<i>P</i><0.01 <i>vs</i>. (-)CLA 1 μmol/L; ^&&<i>P</i><0.01 <i>vs</i>. (-)CLA 1μmol/L; ^@@<i>P</i><0.01 <i>vs</i>. (+)CLA 1μmol/L.</p

Observation of the morphology(A), specific marker (B) and P-gp expression(C) of primary rat brain microvessel endothelial cells(RBMEC), and effects of clausenamide(CLA) enantiomers at different concentrations on the accumulation of rhodamine 123 in the absence(D) or presence(E) of P-gp inhibitor verapamil in the RBMECs.

<p>Data were presented as Mean±SD from 4–5 independent experiments; (-) or (+)CLA: 1 μmol/L; rhodamine123(Rh123): 5 μmol/L; *<i>P</i><0.05, **<i>P</i><0.01 <i>vs</i>. Control; ^#<i>P</i><0.05 <i>vs</i>. (-)CLA; ^&<i>P</i><0.05 <i>vs</i>. (-)CLA 1 μmol/L; ^@@<i>P</i><0.01 <i>vs</i>. (+)CLA.</p