Anion binding with two polyammonium macrocycles of different dimensionality.

A comparative study of the binding of nitrate and sulfate with a polyammonium monocycle L(1), (3,6,9,17,20,23-hexaazatricyclo[23.3.1.1(11,15)]-triaconta-1(29),11,13,15(30),25,27-hexaene), and the corollary bicycle L(2), (1,4,12,15,18,26,31,39-octaazapentacyclo-[13.13.13.1(6,10).1(20,24).1(33,37)]-tetratetraconta-6,7,9,20(43),21,23,33(42),34,36-nonaene), is reported. Potentiometric studies indicated negligible binding for L(1) and nitrate, but high affinity was observed for sulfate (log K(H5L(SO4)/H5L-SO4) = 3.53(1), log K(H6L(SO4)/H6L-SO4) = 4.36(1)). Stronger binding was observed for the cryptand L(2) with both nitrate and sulfate (log K(H6L(NO3)/H6L-NO3) = 3.11(5), log K(H7L(NO3)/H7L-NO3) = 3.55(5); log K(H6L(SO4)/H6L-SO4) = 4.43(1), log K(H7L(SO4)/H7L-SO4) = 4.97(5)). Five crystal structures are reported: the nitrate (1) and sulfate (2) salts of L(1), the free base (3) of L(2), and the nitrate (4) and tosylate (5) salts of L(2). Structural results for L(1) indicate relatively planar monocycles with cis and trans orientations of the phenyl groups for 2 and 1, respectively, with the anions above and below the monocycle rings. For L(2), key features include an encapsulated water and intricate water network in 3, two encapsulated and four external nitrates and two external water molecules in 4, and six external tosylates with sulfonate groups pointing into the cavity and eight external waters in 5.

Enhancement of CsNO3 extraction in 1,2-dichloroethane by tris(2-aminoethyl)amine triamide derivatives via a dual-host strategy

A systematic study of a dual-host system exhibiting pairwise anion/cation separations has been performed for CsNO3 extraction. Tripodal triamides 1-4 and 9 derived from condensation of hexanoic (for 1), octanoic (for 2), decanoic (for 3), lauric (for 4), and p-tert-butylbenzoic (for 9) acid with tris(2-aminoethyl)amine (tren) were used together with tetrabenzo-24-crown-8, a well-known Cs+ cation receptor. By using 5 mM crown ether in the organic phase and 10 mM CsNO3 with 0.1 mM HNO3 in the aqueous phase, tripods 1, 2, and 9 enhance CsNO3 extraction by factors of 2.4, 1.7, and 4.4, respectively (for 50 mM amide concentration), while the corresponding monoamide controls 5-8 derived from n-propylamine (5, 6) or N,N'-dimethylethylenediamine (7, 8) and hexanoic (5, 7) or octanoic (6, 8) acid derivatives gave no significant enhancement under the same conditions. This behavior may be ascribed to nitrate complexation by the triamides, which lowers the overall thermodynamic barrier for the salt transfer to the organic phase. The nitrate binding was confirmed by 1H NMR titration of receptor solutions, using tetrabutylammonium nitrate. Association constants for the formation of the anion-nitrate complexes were found to vary between 33 and 52 M-1 for the more soluble triamides. The synergistic effects for CsNO3 extraction are in reasonable agreement with the values predicted theoretically from the measured association constants. Electrospray ionization mass spectrometry confirmed the predominant formation of 1:1 tripod-nitrate complexes. Monoamide controls gave no evidence of anion complexation.

Cell activation and thrombin generation in heparin bonded cardiopulmonary bypass circuits using a novel in vitro model.

OBJECTIVE: It is generally agreed that when the blood contact surfaces of a cardiopulmonary bypass circuit are treated with a layer of heparin molecules the activation of the humoral pathways is attenuated. However, there is still debate as to whether heparin-bonded circuits reduce thrombin generation. This study aims to examine the effects of immobilized heparin on cell activation and thrombin generation in a novel, well controlled model of cardiopulmonary bypass. METHODS: The model used consisted of a heparin-bonded and a non-bonded cardiopulmonary bypass circuit perfused in tandem with the same unit of fresh heparinized (3.3 U/ml) human blood for a period of 6 h. Samples were taken for analysis from the bag just prior to perfusion and at 30, 60, 120 and 360 min of perfusion. Whole blood was used to analyse platelet and white blood cell count, haematocrit and activated coagulation time. Plasma samples were prepared for batch analysis of the cell activation markers p-selectin, elastase and interleukin-8, and the thrombin generation markers thrombin-antithrombin and prothrombin fragment F1 + 2. A sample of tubing was taken from each circuit at the end of the perfusion and prepared for visualization by scanning electron microscopy. RESULTS: Platelet counts were significantly reduced in the non-bonded circuits compared with the heparin-bonded circuits at 30 (22 versus 200 x 10(9)/L P < 0.01), 60 (26 versus 193 x 10(9)/L P < 0.01) and 120 min (28 versus 193 x 10(9)/L P < 0.01) as were white blood cell counts at 30(1.5 versus 2.7 x 10(9)/L P < 0.01), 60 (0.9 versus 2.4 x 10(9)/L P < 0.01), 120 (0.9 versus 1.8 x 10(9)/L P < 0.01) and 360 min (0.4 versus 0.9 x 10(9)/L P < 0.05). The concentration of p-selectin was found to be significantly higher in the non-bonded circuits than in the heparin-bonded circuits at 30 (37 versus 29 ng/ml P < 0.01), 60 (37 versus 28 ng/ml P < 0.01). 120 (42 versus 27 ng/ml P < 0.01) and at 360 min (72 versus 46 ng/ml P < 0.01). Elastase was elevated in the non-bonded circuits at 30 (570 versus 145 micrograms/l P < 0.01), 60 (646 versus 278 micrograms/l P < 0.01) and 120 min (613 versus 403 micrograms/l P < 0.05) and interleukin-8 at 120 (705 versus 520 pg/ml P < 0.05) and 360 min (11326 versus 9910 pg/ml P < 0.05). A similar picture was found for the thrombin generation markers. Thrombin-antithrombin complexes were raised in the non-bonded circuits compared with heparin-bonded circuits at 60 (24 versus 13 micrograms/l P < 0.05) and 120 min (46 versus 17 micrograms/l P < 0.05) as was prothrombin fragment F1 + 2 at 30 (1.1 versus 0.7 nmol/l P < 0.01), 60 (1.3 versus 0.7 nmol/l P < 0.01), 120 (1.8 versus 0.9 nmol/l P < 0.01) and 360 min (15.0 versus 13.6 nmol/l P < 0.05). Scanning electron microscopy revealed a greater amount of adherent material on the non-bonded surface relative to the heparin-bonded surface. CONCLUSIONS: In a cardiopulmonary bypass circuit perfused with human blood the activation of platelets and white blood cells has been seen to be significantly reduced in the presence of a heparin-bonded surface. Thrombin generation due to contact activation of the intrinsic coagulation pathway is also reduced.

Low heparinization with heparin-bonded bypass circuits: is it a safe strategy?

BACKGROUND: The use of heparin-bonded cardiopulmonary bypass circuits with reduced doses of heparin sodium has been shown to give hemostatic benefits to the patient. However, fears persist that the use of less heparin may put the patient at risk for thrombotic events. This work tested the hypothesis that heparin-bonded circuits per se are effective in preserving cells and reducing thrombin generation when a reduced dose of heparin is used in vitro. METHODS: Simulated extracorporeal circulation was carried out using the same unit of fresh heparinized (1.1 U/mL) human blood to simultaneously perfuse a heparin-bonded circuit and a nonbonded circuit. Samples were taken at 30, 60, 120, and 360 minutes and analyzed for markers of cell activation and thrombin generation. RESULTS: The concentrations of platelet and white blood cell activation markers were found to be significantly lower in the heparin-bonded circuits compared with the nonbonded circuits. In addition, markers of thrombin generation were significantly lower in bonded circuits. Scanning electron microscopy revealed fewer adherent cells and less debris on the bonded surface compared with the nonbonded surface. CONCLUSIONS: Cell activation and thrombin generation were significantly reduced as a result of the presence of immobilized heparin in a system of cardiopulmonary bypass with reduced plasma heparin. However, evidence of contact activation in the bonded circuits was found after 120 minutes, indicating that anticoagulation in the system was not adequate. This becomes more important clinically where the extrinsic pathway of coagulation is also involved.