Stereoselective Modulation of P-Glycoprotein by Chiral Small Molecules.

Inhibition of drug efflux pumps such as P-glycoprotein (P-gp) is an approach toward combating multidrug resistance, which is a significant hurdle in current cancer treatments. To address this, N-substituted aryloxymethyl pyrrolidines were designed and synthesized in their homochiral forms in order to investigate the stereochemical requirements for the binding site of P-gp. Our study provides evidence that the chiral property of molecules could be a strategy for improving the capacity for interacting with P-gp, as the most active compounds of the series stereoselectively modulated this efflux pump. The naphthalene-1-yl analogue (R)-2-[(2,3-dichlorophenoxy)methyl]-1-(naphthalen-1-ylmethyl)pyrrolidine) [(R)-7 a] emerged foremost for its potency and stereoselectivity toward P-gp, with the S enantiomer being nearly inactive. The modulation of P-gp by (R)-7 a involved consumption of ATP, thus demonstrating that the compound behaves as a P-gp substrate.

Blood cell counting in neonates: a comparison between a low volume micromethod and the standard laboratory method.

BACKGROUND: Iatrogenic anaemia caused by repeated blood sampling to monitor laboratory parameters can contribute, particularly in neonates, to the need for transfusion. "Point of care" laboratory equipment uses smaller amounts of blood for analytic determinations and could, therefore, help to prevent secondary anaemia. In this study we compared the results of haematological parameters measured using a standard laboratory method and using a "point of care" micromethod, with the aim of validating the use of this latter method in clinical practice in neonatology. MATERIALS AND METHODS: One hundred and fifty venous or capillary blood samples were taken from full-term or premature neonates 2-4 hours or 48 hours after birth. Each sample was processed by a standard haematology analyser and another micromethod instrument. Bland-Altman plots were constructed for each parameter and intra-class coefficients of correlation were calculated in order to evaluate the concordance between the two analysers. RESULTS: The concordance between the data obtained with the two analysers, expressed as the intra-class correlation, was 0.98 for white blood cell count, 0.97 for haemoglobin concentration, 0.96 for haematocrit, 0.95 for mean red cell volume and 0.98 for platelet count. The micromethod produced overestimated mean values for the leucocyte count (+1.27; p<0.001), haematocrit (+1.80; p<0.001) and platelet count (+13.55; p<0.001). CONCLUSIONS: Overall, the concordance between the values obtained with the two analysers was high for each of the parameters taken into consideration. In the case of haemoglobin and leucocytes, give the high intra-class correlation and lack of systematic overestimation of one method over another, the micromethod guarantees a correct evaluation; however, despite the high intra-class correlations for platelet counts, the systemic error seems to suggest that the micromethod cannot guarantee an appropriate evaluation of this parameter.