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.     

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.     

Eliminating memory for fragmentation within partitionable SIMD/SPMDmachines

Efficient data layout is an important aspect of the compilation process. A model for the creation of perfect memory maps for large-scale parallel machines capable of user-controlled partitionable single-instruction-multiple data/single-program-multiple data (SIMD/SPMD) operation is developed. The term perfect implies that no memory fragmentation occurs and ensures that the memory map size is kept to a minimum. A major constraint on solving this problem is based on the single program nature of both the SIMD and SPMD modes of parallelism. It is assumed that all processors within the same submachine used identical addresses to access corresponding data items in each of their local memories. Necessary and sufficient conditions are derived for being able to create perfect memory maps, and results are applied to several partitionable interconnection networks     

SlideBar: Analysis of a linear input device

The SlideBar is a physical linear input device for absolute position control of 1° of freedom, consisting of a physical slider with a graspable knob positioned near or attached to the keyboard. Its range of motion is directly mapped to a one dimensional input widget such as a scrollbar. The SlideBar provides absolute position control in one dimension, is usable in the non-dominant hand in conjunction with a pointing device, and offers constrained passive haptic feedback. These characteristics make the device appropriate for the common class of tasks characterized by one-dimensional input and constrained range of operation. An empirical study of three devices (SlideBar, mouse controlled scrollbar, and mousewheel) shows that for common scrolling tasks, the SlideBar has a significant advantage over a standard mouse controlled scrollbar in user preference. In addition, users tended to prefer it over the mousewheel (without statistical significance).     

Reduction of Radiation-Induced Hair Loss by Topical Application of Radioprotectors

ABSTRACT

Our transdermal permeation studies of radioprotectors in permeation-enhancing vehicles led us to hypothesize that radiation-induced hair loss could be reduced by topical application of radioprotectors. In the present study we used a hair regrowth assay in “plucked” mice to measure the radioprotective effectiveness of WR-1065, cysteine and TEMPOL when they were dissolved in a variety of vehicles, i.e., saline, dimethyl formamide (DMF), propylene glycol (PG), dimethyl sulfoxide (DMSO), ethanol. Protector effectiveness varied with radiation dose and vehicles. At 600 R, WR-1065 or cysteine, in any vehicle, reduced radiation-induced baldness scores; at 800 R, only WR-1065 in DMF and cysteine in saline, produced some protection. TEMPOL in ethanol produced protection at both the 600 and 800 R. Results suggest that suitably chosen topical application of protector/vehicle combinations can reduce radiation-induced hair loss.     

A Tale of Two Cities: Financing Two Voucher Programs for Substance Abusers Through Community Donations.

Voucher-based reinforcement therapy (VBRT) is an effective drug abuse treatment, but the cost of VBRT rewards has limited its dissemination. Obtaining VBRT incentives through donations may be one way to overcome this barrier. Two direct mail campaigns solicited donations for use in VBRT for pregnant, postpartum, and parenting drug users in Toronto, Ontario, Canada, and in Los Angeles, California. In Toronto, 19% of those contacted over 2 months donated $8,000 ($4,000/month) of goods and services. In Los Angeles, nearly 26% of those contacted over 34 months donated $161,000 ($4,472/month) of goods and services. Maintaining voucher programs by soliciting donations is feasible and sustainable. The methods in this article can serve as a guide for successful donation solicitation campaigns. Donations offer an alternative for obtaining VBRT rewards for substance abuse treatment and may increase its dissemination. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Appraisal as a Pervasive Determinant of Anger.

L. Berkowitz and E. Harmon-Jones (see record 2004-15096-001) challenge appraisal theories of emotion by describing 2 sets of conditions (physical discomfort and anger-related muscle actions) in which anger appears to be elicited in the absence of theoretically predicted appraisals. In response, the authors discuss the ability of the specific appraisal model they have developed (e.g., C. A. Smith & L. D. Kirby, 2000, 2001; C. A. Smith & R. S. Lazarus, 1990) to account for such instances of anger. First, a number of issues are clarified relevant to the authors' model, including the nature of both the cognitive operations underlying appraisal and the specific appraisals hypothesized to evoke anger. The authors then describe how their model can account for the instances of anger described by L. Berkowitz and E. Harmon-Jones and how both accounts might be tested. (PsycINFO Database Record (c) 2010 APA, all rights reserved)