The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

A multigrid accelerated hybrid unstructured mesh method for 3D compressible turbulent flow

 A cell vertex finite volume method for the solution of steady compressible turbulent flow problems on unstructured hybrid meshes of tetrahedra, prisms, pyramids and hexahedra is described. These hybrid meshes are constructed by firstly discretising the computational domain using tetrahedral elements and then by merging certain tetrahedra. A one equation turbulence model is employed and the solution of the steady flow equations is obtained by explicit relaxation. The solution process is accelerated by the addition of a multigrid method, in which the coarse meshes are generated by agglomeration, and by parallelisation. The approach is shown to be effective for the simulation of a number of 3D flows of current practical interest. Sponsored by The Research Council of Norway, project number 125676/410 Dedicated to the memory of Prof. Mike Crisfield, a respected colleague     

Experimental evidence of a relationship between monomer plasma residence time and carboxyl group retention in acrylic acid plasma polymers

Decreasing carboxyl retention in deposits from the glow region of an acrylic acid plasma was measured by X-ray photoelectron spectroscopy and chemical derivatisation as the collection distance from the monomer vapour inlet was increased. Volatilisation of plasma polymerised acrylic acid was detected after trifluoroethanol derivatisation; this is correlated with evaporation of low molecular weight components observed previously.     

Solving ML equations for 2-parameter Poisson-process models forungrouped software-failure data

Existence conditions are given for maximum likelihood (ML) parameter estimates for several families of 2-parameter software-reliability Poisson-process models. For each such model, the ML equations can be expressed in terms of one equation in one unknown. Bounds are given on solutions to these one equation problems to serve as initial intervals for search algorithms like bisection. Uniqueness of the solutions is established in some cases. Solutions are also tabulated for certain simple cases. Results are given for ungrouped failure data (exact times are available for all failures). ML estimation problems for such a situation are treated as limiting cases of problems based on failure times grouped into intervals of decreasing mesh     

The ‘Hoare logic’ of concurrent programs

Summary Hoare's logical system for specifying and proving partial correctness properties of sequential programs is generalized to concurrent programs. The basic idea is to define the assertion {P} S {Q} to mean that if execution is begun anywhere in S with P true, then P will remain true until S terminates, and Q will be true if and when S terminates. The predicates P and Q may depend upon program control locations as well as upon the values of variables. A system of inference rules and axiom schemas is given, and a formal correctness proof for a simple program is outlined. We show that by specifying certain requirements for the unimplemented parts, correctness properties can be proved without completely implementing the program. The relation to Pnueli's temporal logic formalism is also discussed.     

Phase Studies Concerning Sintering in Aluminas Doped with Ti4+

Previous solid state analyses of sintering in Ti⁴⁺-doped-commercial alumina are shown to be in error because a liquid phase exists in the appropriate region of the Al₂O₃−TiO₃−Na₂Ophase diagram at least by 1350^°C, a temperature lower than that at which "solid state" studies were conducted. It is suggested that liquid-phase sintering is a much more common occurrence than was realized formerly.