Looking in the rear view mirror when conversing with back seat drivers: the EXCITE trial revisited

The initial point of view: Directions for Research (Neurorehabilitation and Neural Repair, 2007;21:3-13) identified confounders that might limit the impact that rehabilitation multicenter clinical trials may have upon altering practice patterns. Part of that viewpoint addressed the Extremity Constraint Induced Therapy Evaluation (EXCITE) Trial and highlighted some of its perceived strengths and limitations. The present Point of View expands upon factors worthy of consideration in planning and executing clinical trials in neurorehabilitation based upon experiences encountered by the EXCITE team. Cost factors and patient attributes, both of which profoundly influence the ability of clinical researchers to execute the ideal study, are among these factors. In particular, the costs associated with large trials necessitate compromise in study design or implementation, resulting in a dichotomy between what should be undertaken and what can be accomplished.     

Does the cholinesterase inhibitor, donepezil, benefit both declarative and non-declarative processes in mild to moderate Alzheimer's disease?

Previous research suggests separate neural networks for implicit (non-declarative) and explicit (declarative) memory processes. A core cognitive impairment in mild to moderate Alzheimer's disease (AD) is a pronounced declarative memory and learning deficit with relative preservation of non-declarative memory. Cholinesterase inhibitors has been purported to enhance cognitive function, and previous clinical trials consistently showed that donepezil, a reversible inhibitor of acetylcholinesterase (AChE), led to statistically significant improvements in cognition and patient function. This prospective pilot study is a randomized, double blind, placebo-controlled clinical trial investigating 10 patients with AD. Our purpose was to examine the relationship between declarative and non-declarative capability with particular emphasis on implicit sequence learning. Patients were assessed at baseline and again at 4-weeks. After participants' baseline data were obtained, each was double-blindly randomized to one of two groups: donepezil or placebo. At baseline participants were tested with two outcome measures (Serial Reaction Time Task, Alzheimer's Disease Assessment Scale-Cognitive Subscale). Participants were given either 5 mg donepezil or an identically appearing placebo to be taken nightly for 4 weeks (28 tablets), and then retested. The donepezil group demonstrated a greater likelihood of increases in both non-declarative and declarative processes. The placebo group was mixed without clearly definable trends or patterns. When the data were examined for coincidental changes in the two outcome measures together they are suggestive of a benefit from donepezil treatment for non-declarative and declarative processes.     

Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial

Context  Single-site studies suggest that a 2-week program of constraint-induced movement therapy (CIMT) for patients more than 1 year after stroke who maintain some hand and wrist movement can improve upper extremity function that persists for at least 1 year. Objective  To compare the effects of a 2-week multisite program of CIMT vs usual and customary care on improvement in upper extremity function among patients who had a first stroke within the previous 3 to 9 months. Design and Setting  The Extremity Constraint Induced Therapy Evaluation (EXCITE) trial, a prospective, single-blind, randomized, multisite clinical trial conducted at 7 US academic institutions between January 2001 and January 2003. Participants  Two hundred twenty-two individuals with predominantly ischemic stroke. Interventions  Participants were assigned to receive either CIMT (n = 106; wearing a restraining mitt on the less-affected hand while engaging in repetitive task practice and behavioral shaping with the hemiplegic hand) or usual and customary care (n = 116; ranging from no treatment after concluding formal rehabilitation to pharmacologic or physiotherapeutic interventions); patients were stratified by sex, prestroke dominant side, side of stroke, and level of paretic arm function. Main Outcome Measures  The Wolf Motor Function Test (WMFT), a measure of laboratory time and strength-based ability and quality of movement (functional ability), and the Motor Activity Log (MAL), a measure of how well and how often 30 common daily activities are performed. Results  From baseline to 12 months, the CIMT group showed greater improvements than the control group in both the WMFT Performance Time (decrease in mean time from 19.3 seconds to 9.3 seconds [52% reduction] vs from 24.0 seconds to 17.7 seconds [26% reduction]; between-group difference, 34% [95% confidence interval {CI}, 12%-51%]; P<.001) and in the MAL Amount of Use (on a 0-5 scale, increase from 1.21 to 2.13 vs from 1.15 to 1.65; between-group difference, 0.43 [95% CI, 0.05-0.80]; P<.001) and MAL Quality of Movement (on a 0-5 scale, increase from 1.26 to 2.23 vs 1.18 to 1.66; between-group difference, 0.48 [95% CI, 0.13-0.84]; P<.001). The CIMT group achieved a decrease of 19.5 in self-perceived hand function difficulty (Stroke Impact Scale hand domain) vs a decrease of 10.1 for the control group (between-group difference, 9.42 [95% CI, 0.27-18.57]; P=.05). Conclusion  Among patients who had a stroke within the previous 3 to 9 months, CIMT produced statistically significant and clinically relevant improvements in arm motor function that persisted for at least 1 year. Trial Registration  clinicaltrials.gov Identifier: NCT00057018      

Design,synthesis, and biological evaluation of indolequinone phosphoramidate prodrugs targeted to DT-diaphorase

A series of 2- and 3-substituted indolequinone phosphoramidate prodrugs targeted to DT-diaphorase (DTD) have been synthesized and evaluated. These compounds are designed to undergo activation via quinone reduction by DTD followed by expulsion of the phosphoramide mustard substituent from the hydroquinone. Chemical reduction of the phosphoramidate prodrugs led to rapid expulsion of the corresponding phosphoramidate anions in both series of compounds. Compounds substituted at the 2-position are excellent substrates for human DTD (k(cat)/K(M) = (2-5) x 10(6) M(-1) s(-1)); however, compounds substituted at the 3-position are potent inhibitors of the target enzyme. Both series of compounds are toxic in HT-29 and BE human colon cancer cell lines in a clonogenic assay. There was a correlation found between cytotoxicity and DTD activity for the 2-series of phosphoramidates; however, there was no correlation between cytotoxicity and DTD activity in the 3-series of compounds. This finding suggests the presence of an alternative mechanism for the activation of these compounds.     

Oral Nicotine in Treatment of Primary Sclerosing Cholangitis (A Pilot Study)

Currently, no accepted medical therapy forpatients with primary sclerosing cholangitis (PSC) isavailable. Case-control studies have shown an inverseassociation between PSC and smoking behavior, suggesting that nicotine might have a beneficial effect inPSC. The aim of this study was to evaluate the safetyand estimate the efficacy of oral nicotine in thetreatment of PSC. Eight PSC patients who had never smoked received oral nicotine at a maximum doseof 6 mg four times a day for up to one year. Liverbiochemistries and plasma cotinine levels weredetermined at entry and at three-month intervals during the study duration. Five patients completed oneyear of treatment, but three of them had to temporarilyreduce the dose due to side effects. One patientcompleted only four months of treatment due to dizziness and heart palpitations. Two patients completedonly one month of treatment due to reactivation ofcolitis requiring corticosteroid therapy. No significantchanges in liver biochemistries were noted during the treatment period despite a significantincrease in plasma cotinine levels. In conclusion, oralnicotine seems to have no beneficial effects in thetreatment of PSC, and it is frequently associated with side effects necessitating permanent drugcessation.     

Lenticular meridional astigmatism secondary to iris mesectodermal leiomyoma

A 61-year-old African American man presented with decreased vision of 2 months duration. Examination revealed a significant lenticular astigmatism and sectoral cataract as a result of an amelanotic iris lesion. Slitlamp optical coherence tomography (OCT) revealed angle crowding. An excisional biopsy was performed along with phacoemulsification in the right eye, with intraocular lens implantation for meridional lenticular astigmatism. Histopathology and histoimmunochemistry confirmed a diagnosis of uveal mesectodermal leiomyoma. Lenticular astigmatism may be a subtle sign of an anterior segment tumor. Anterior segment slitlamp OCT is an effective tool in diagnosing as well as monitoring small interval changes in these types of tumors.