Prolonged and tunable residence time using reversible covalent kinase inhibitors.

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo

Clinical indications for digital imaging in dento-alveolar trauma. Part 1: traumatic injuries

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73819/1/j.1600-9657.2006.00509.x.pd

Parental Misinterpretations of Over-the-Counter Pediatric Cough and Cold Medication Labels

Concerns about the safety and efficacy of over-the-counter cold medications have led to a recent US Food and Drug Administration public health advisory against their use in children <2 years of age. Our goal was to examine caregiver understanding of the age indication of over-the-counter cold medication labels and identify factors, associated with caregiver understanding

Characterizing a source of fission fragments for a gas jet

A model for the rate at which various primary fission products stop in the gas of the source chamber of a gas jet has been constructed. It describes the absorption of fission fragments in Al foils placed between the 235 U deposit and the gas chamber as well as the penetration of fragments through the gas. The model is based on reported ranges (mean values as a function of A and the dispersion in ranges) and measured activities of Kr and Xe.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43112/1/10967_2005_Article_BF02060552.pd

Management of toxic ingestions with the use of renal replacement therapy

Although rare, renal replacement therapy (RRT) for the treatment of the metabolic, respiratory and hemodynamic complications of intoxications may be required. Understanding the natural clearance of the medications along with their volume of distribution, protein binding and molecular weight will help in understanding the benefit of commencing RRT. This information will aid in choosing the optimal forms of RRT in an urgent setting. Overdose of common pediatric medications are discussed with suggestions on the type of RRT within this educational review