This review describes simple and useful concepts for predicting and tuning the pK(a) values of basic amine centers, a crucial step in the optimization of physical and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pK(a) values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chemistry. Next, the changes in pK(a) of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivatives are systematically analyzed, leading to the derivation of simple rules for pK(a) prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pK(a) predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.

Children with hemiplegic cerebral palsy (CP) have impairments in bimanual coordination above and beyond their unilateral impairments. Recently we developed hand‐arm bimanual intensive therapy (HABIT), using the principles of motor learning, and neuroplasticity, to address these bimanual impairments. A single‐blinded randomized control study of HABIT was performed to examine its efficacy in children with hemiplegic CP with mild to moderate hand involvement. Twenty children (age range 3y 6mo‐15y 6mo) were randomized to either an intervention (n=10: seven males, three females; mean age 8y 7mo, SD 4y) or a delayed treatment control group (n=10: seven males, three females; mean age 6y 10mo, SD 2y 4mo). Children were engaged in play and functional activities that provided structured bimanual practice 6 hours per day for 10 days. Each child was evaluated immediately before and after the intervention, and again at 1‐month post‐intervention. Children in the intervention group demonstrated improved scores on the Assisting Hand Assessment, increased involved extremity use measured using accelerometry and a caregiver survey, bimanual items of the Bruininks–Oseretsky Test of Motor Proficiency, and the simultaneity of completing a draw‐opening task with two hands (p<0.05 in all cases). The results suggest that for this carefully selected subgroup of children with hemiplegic CP, HABIT appears to be efficacious in improving bimanual hand use.

Constraint-induced (CI) movement therapy is a promising therapy for improving upper limb function in adults after stroke. It involves restraint of the non-involved limb and extensive movement practice with the involved limb. In this study, a single-blinded, randomized, control study was performed to examine the efficacy of CI therapy, modified to be child friendly, in children with hemiplegic cerebral palsy (CP). Twenty-two children (8 females, 14 males; mean age 6 y 8 mo [SD 1 y 4 mo]; range 4-8 y) were randomized to either an intervention group (n=11) or a delayed treatment control group (n=11). Children wore a sling on their non-involved upper limb for 6 hours per day for 10 out of 12 consecutive days and were engaged in play and functional activities. Children in the treatment group demonstrated improved movement efficiency and dexterity of the involved upper extremity, which were sustained through the 6-month evaluation period, as measured by the Jebsen-Taylor Test of Hand Function and fine motor-subtests of the Bruininks-Oseretsky Test of Motor Proficiency (p<0.05 in both cases). Initial severity of hand impairment and testing compliance were strong predictors of improvement. Caregivers reported significant increases in involved limb frequency of use and quality of movement. However, there was no change in strength, sensibility, or muscle tone (p>0.05 in all cases). Results suggest that for a carefully selected subgroup of children with hemiplegic CP, CI therapy modified to be child-friendly, appears to be efficacious in improving movement efficiency of the involved upper extremity.

Vertex Pharmaceuticals Incorporated.

Constraint‐induced (CI) movement therapy is a promising therapy for improving upper limb function in adults after stroke. It involves restraint of the non‐involved limb and extensive movement practice with the involved limb. In this study, a single‐blinded, randomized, control study was performed to examine the efficacy of CI therapy, modified to be child friendly, in children with hemiplegic cerebral palsy (CP). Twenty‐two children (8 females, 14 males; mean age 6y 8mo [SD 1y 4mo]; range 4–8y) were randomized to either an intervention group (n= 11) or a delayed treatment control group (n= 11). Children wore a sling on their non‐involved upper limb for 6 hours per day for 10 out of 12 consecutive days and were engaged in play and functional activities. Children in the treatment group demonstrated improved movement efficiency and dexterity of the involved upper extremity, which were sustained through the 6‐month evaluation period, as measured by the Jebsen‐Taylor Test of Hand Function and fine motor‐subtests of the Bruininks‐Oseretsky Test of Motor Proficiency (p < 0.05 in both cases). Initial severity of hand impairment and testing compliance were strong predictors of improvement. Caregivers reported significant increases in involved limb frequency of use and quality of movement. However, there was no change in strength, sensibility, or muscle tone (p > 0.05 in all cases). Results suggest that for a carefully selected subgroup of children with hemiplegic C P, CI therapy modified to be child‐friendly, appears to be efficacious in improving movement efficiency of the involved upper extremity.