Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872)

MK-0991 (L-743,872) is a potent antifungal agent featuring long half-life pharmacokinetics. The pharmacokinetics of MK-0991 administered intravenously to mice, rats, rhesus monkeys, and chimpanzees is presented. Unique to MK-0991 is its consistent cross-species performance. The range of values for the pharmacokinetic parameters were as follows: clearance, 0.26 to 0.51 ml/min/kg; half-life, 5.2 to 7.6 h; and distributive volume, 0.11 to 0.27 liters/kg. The level of protein binding of MK-0991 was determined to be 96% in mouse and human serum. The compound exhibited high affinities for human serum albumin and at least two lipid components. The rationale for the selection of MK-0991 as a drug development candidate was based on its two- to threefold superior pharmacokinetic performance in chimpanzees over the performance of an otherwise equivalent analog, L-733,560. Once-daily dosing for MK-0991 is indicated by a graphical comparison of levels in the circulations of chimpanzees and mice. In a study of the pharmacokinetics of MK-0991 in mouse tissue, the organs were assayed following intraperitoneal administration. The area under the concentration-versus-time curves (AUC) segregated the tissues into three exposure categories relative to plasma. The tissues with greater exposure than that for plasma were liver (16 times), kidney (3 times), and large intestine (2 times). The exposure for small intestine, lung, and spleen were equivalent to that for plasma. Organs with lower levels of exposure were the heart (0.3 times that for plasma), thigh (0.2 times), and brain (0.06 times). Kinetically, drug was cleared more slowly from all tissues than from plasma, indicating that terminal-phase equilibrium had not been achieved by 24 h. Thus, some measure of accumulation is predicted for all tissues. Single daily doses of MK-0991 should provide adequate systemic levels of fungicidal activity as a result of its long half-life pharmacokinetics, wide distribution, and slowly accumulating concentrations in tissue.     

The Use of Different Conveyance Calculations for Modelling Flows in a Compact Compound Channel

Flow measurements have been taken for steady and unsteady flows on a reach of a river having a compact compound channel. The 'single channel', 'divided channel' and 'lateral' distribution methods have been used to calculate conveyances for use in a one-dimensional unsteady flow model of the reach. Comparisons with measured flows show that the divided channel method and the lateral distribution method both underestimate floodplain flow depths. The lateral distribution method gives the closest accuracy in the relative depth range 0.15 ≤ Yr < 0.40. For large flow depths the single channel method becomes more accurate and slightly over-estimates flow depths.
The accuracy of unit width discharge distributions, calculated from the lateral distribution method are assessed by comparison with observed distributions for overbank flows.     

Tradeable Rights for Water Abstraction

The Environment Agency has a statutory duty to secure the proper use of water resources, which is now considered inter alia to include an economically efficient allocation of resources as far as is possible within the current legislation. This paper considers the practical extent to which water rights can be traded within the existing system of regulation as a means of (a) improving the economic efficiency of resource allocation, and (b) satisfying customer demand for additional supplies. Outline proposals are also made for deregulation of current legislation to encourage further trading through less restrictive regulation.     

原料摩尔比对硫氧镁胶凝材料性能的影响

研究了氧化镁-硫酸镁摩尔比n(MgO)/n(MgSO4),水-硫酸镁摩尔比n(H2O)/n(MgSO4)对硫氧镁胶凝材料性能的影响及其微观机理.结果表明:固定n(H2O)/n(MgSO4)为19∶1,n(MgO)/n(MgSO4)为14∶1时硫氧镁胶凝材料力学性能最优;n(MgO)/n(MgSO4)超过14∶1后,硫氧镁胶硬化浆体中剩余MgO和Mg(OH)2的含量会增大,使硬化结构疏松,从而降低其力学性能;固定n(MgO)/n(MgSO4)为14∶1时,n(H2O)/n(MgSO4)的增大会延缓硬化硫氧镁浆体中碱式硫酸镁相的生成,造成微观结构中产生大量孔隙,从而导致其力学性能下降.