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.     

Management, Market, and Financial Factors Separating Winners and Losers in E-Business

There have been many successful e‐businesses as well as many failed e‐businesses. The methods and practices that were evident in the development of both surviving e‐businesses and failed ones have much to teach us. Why did some e‐businesses fail while others survived? At present few guidelines exist to assist e‐business owners and managers wanting to succeed in their Internet‐based ventures. This study empirically investigated factors that may lead to e‐business success or failure; these were categorized as management, market, and financial factors. The results of a survey were combined with one‐on‐one interviews of venture capitalists who funded successful and failed e‐businesses. The results indicate that certain factors deemed applicable to an e‐business may have contributed to the firm’s eventual success or failure.     

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.     

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.     

Perceived self-efficacy and pain control: Opioid and nonopioid mechanisms.

In this experiment, we tested for opioid and nonopioid mechanisms of pain control through cognitive means and the relation of opioid involvement to perceived coping efficacy. Subjects were taught cognitive methods of pain control, were administered a placebo, or received no intervention. Their pain tolerance was then measured at periodic intervals after they were administered either a saline solution or naloxone, an opiate antagonist that blocks the effects of endogenous opiates. Training in cognitive control strengthened perceived self-efficacy both to withstand and to reduce pain; placebo medication enhanced perceived efficacy to withstand pain but not reductive efficacy; and neither form of perceived self-efficacy changed without any intervention. Regardless of condition, the stronger the perceived self-efficacy to withstand pain, the longer subjects endured mounting pain stimulation. The findings provide evidence that attenuation of the impact of pain stimulation through cognitive control is mediated by both opioid and nonopioid mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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)