Kinase inhibitors for the treatment of inflammatory and autoimmune disorders

Drugs targeting inhibition of kinases for the treatment of inflammation and autoimmune disorders have become a major focus in the pharmaceutical and biotech industry. Multiple kinases from different pathways have been the targets of interest in this endeavor. This review describes some of the recent developments in the search for inhibitors of IKK2, Syk, Lck, and JAK3 kinases. It is anticipated that some of these compounds or newer inhibitors of these kinases will be approved for the treatment of rheumatoid arthritis, psoriasis, organ transplantation, and other autoimmune diseases

Designing an iPad App to Monitor and Improve Classroom Behavior for Children with ADHD: iSelfControl Feasibility and Pilot Studies

Children with Attention Deficit/Hyperactivity Disorder (ADHD) receive approximately 80% of instruction in the general education classroom, where individualized behavioral management strategies may be difficult for teachers to consistently deliver. Mobile device apps provide promising platforms to manage behavior. This pilot study evaluated the utility of a web-based application (iSelfControl) designed to support classroom behavior management. iSelfControl prompted students every 'Center' (30-minutes) to self-evaluate using a universal token-economy classroom management system focused on compliance, productivity, and positive relationships. Simultaneously, the teacher evaluated each student on a separate iPad. Using Multi Level Modeling, we examined 13 days of data gathered from implementation with 5th grade students (N = 12) at a school for children with ADHD and related executive function difficulties. First, an unconditional growth model evaluated the overall amount of change in aggregated scores over time as well as the degree of systematic variation in scores within and across teacher-student dyads. Second, separate intercepts and slopes were estimated for teacher and student to estimate degree of congruency between trajectories. Finally, differences between teacher and student scores were tested at each time-point in separate models to examine unique 'Center' effects. 51% of the total variance in scores was attributed to differences between dyads. Trajectories of student and teacher scores remained relatively stable across seven time-points each day and did not statistically differ from each other. On any given day, students tended to evaluate their behaviors more positively (entered higher scores for themselves) compared to corresponding teacher scores. In summary, iSelfControl provides a platform for self and teacher evaluation that is an important adjunct to conventional classroom management strategies. The application captured teacher/student discrepancies and significant variations across the day. Future research with a larger, clinically diagnosed sample in multiple classrooms is needed to assess generalizability to a wider variety of classroom settings

Partial Agonists of the α3β4* Neuronal Nicotinic Acetylcholine Receptor Reduce Ethanol Consumption and Seeking in Rats

Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors (nAChRs) have a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3–CHRNA5–CHRNB4 encoding the α3, α5, and β4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the α3, and β4 subunits of the nAChR in ethanol self-administration, we developed and characterized high-affinity partial agonists at α3β4 nAChRs, CP-601932, and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at α3β4 nAChRs correlate with their unbound rat brain concentrations, suggesting that the effects on ethanol self-administration are mediated via interaction with α3β4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with α3β4 nAChRs. Furthermore, the selective α4β2* nAChR antagonist, DHβE, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies, implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs