Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit

Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including “wearing‐off” and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)‐approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ‐conjugated constructs (“fast”: SER‐212; “moderate”: SER‐213; and “slow”: SER‐214) using in vitro hydrolysis, normal male Sprague‐Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6‐hydroxydopamine (6‐OHDA) infusions, treated acutely with POZ‐rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ‐rotigotine formulations SER‐213 and SER‐214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER‐214 led to antiparkinsonian effects in DA‐lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER‐214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER‐214 could represent a significant advance in the treatment of PD, with potential to be a viable, once‐per‐week therapy for PD patients.     

Reduced frontal white matter integrity in early-onset schizophrenia: a preliminary study.

BACKGROUND: Research suggests that brain frontal white matter (WM) might be qualitatively altered in adolescents with early onset schizophrenia (EOS). Diffusion tensor imaging provides a relatively new approach for quantifying possible connectivity of WM in vivo. METHODS: Diffusion tensor imaging was used to examine the WM integrity of frontal regions at seven levels from 25 mm above to 5 mm below the anterior commissure-posterior commissure (AC-PC) plane. Three other regions were examined: the occipital region at the AC-PC plane and the genu and splenium of the corpus callosum. Fractional anisotropy was compared between 12 adolescents (nine male, 3 female) with EOS (onset of psychotic symptoms by age 18 years) and nine age-similar healthy comparison subjects (six male, 3 female). RESULTS: Adolescents with EOS had significantly reduced fractional anisotropy in the frontal WM at the AC-PC plane in both hemispheres and in the occipital WM at the AC-PC plane in the right hemisphere. CONCLUSIONS: These preliminary data support a hypothesis that alterations in brain WM integrity occur in adolescents with EOS. Abnormalities found in this study were similar to those reported in adults with chronic schizophrenia. Additional studies are needed to assess whether there is progression of WM abnormalities in schizophrenia.     

Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency

We compared neurocognitive indices with clinical status, mutation analysis, and urea synthetic capacity in 19 women heterozygous for ornithine transcarbamylase deficiency. Although as a group, these women had average IQ scores, they displayed a specific neuropsychological phenotype with significant strengths in verbal intelligence, verbal learning, verbal memory, and reading, and significant weaknesses in fine motor dexterity/speed and nonsignificant weaknesses in nonverbal intelligence, visual memory, attention/executive skills, and math. This suggests selective vulnerability of white matter and better preservation of gray matter. When the group was divided into symptomatic and asymptomatic subgroups, based on either clinical history or residual urea synthetic capacity, the asymptomatic subgroup outperformed the symptomatic subgroup on all tested domains of neuropsychological functioning. Furthermore, the amount of residual urea synthetic capacity was predictive of several end point cognitive measures. There was no correlation between neonatal versus late-onset mutation or between normal or abnormal allopurinol challenge and neuropsychological outcome. In sum, we identified a specific metabolic and neurocognitive phenotype in women heterozygous for ornithine transcarbamylase deficiency. The findings support the importance of maintaining meticulous metabolic control in children with urea cycle disorders, because even mildly symptomatic subjects demonstrate cognitive deficits.     

Deficits in memory strategy use are related to verbal memory impairments in adolescents with schizophrenia-spectrum disorders

OBJECTIVE: To assess the nature of learning and verbal memory deficits in adolescents with schizophrenia-spectrum disorders (SzS) (i.e., schizophrenia, schizoaffective disorder, and schizophreniform disorder). METHOD: Sixty patients with SzS (mean age=16.1 years, S.D. = 2.2) and 60 age- and gender-matched diagnosis-free healthy volunteers were assessed using the California Verbal Learning Test (CVLT). Planned analyses were conducted to assess the following aspects of memory: span of apprehension, verbal learning, short-term and long-term memory, rate of forgetting, interference, and organizational strategies. Adolescents with schizophrenia (Sz) were compared to those with schizoaffective disorder (SzA). Second, patients' test profiles were compared to those of controls. Relationships between initial learning and overall verbal learning with organizational strategy were explored. RESULTS: Neurocognitive profiles did not significantly differ between Sz and SzA participants. Patients performed significantly worse than healthy comparison subjects on measures of span of apprehension, verbal learning, short- and long-term memory, and organizational strategies after adjusting for differences in premorbid intelligence. No group differences were found in rate of forgetting or susceptibility to proactive or retroactive interference. CONCLUSIONS: Adolescents with SzS are characterized by significant verbal memory dysfunction similar to what has been observed in adults with first-episode schizophrenia. Deficits in consistency of learning over several trials, as well as a strong relationship between semantic organizational strategies and reduced learning capacity, implicate dysfunction of the dorsolateral prefrontal cortex as a contributor to verbal memory deficits in adolescents with SzS.     

Evaluation of a social-skills training group intervention with children treated for brain tumors: a pilot study

OBJECTIVE: To evaluate the effectiveness of a manual-based, social-skills training, group intervention to improve social skills and social functioning of children treated for brain tumors, and to assess the impact of cognitive functioning on the effectiveness of the intervention. METHODS: Three social-skills training group interventions, each comprised of 5 to 7 children ages 8 to 14 years, were conducted. A parent component was included. In total, 13 children and their parents and teachers completed standard measures prior to and 9 months after the intervention. Children participated in a neuropsychological test battery at baseline. RESULTS: Social skills and social functioning variables changed in the direction of improved functioning, with several scores showing significant improvement from baseline to the follow-up assessment. Small to medium effect sizes were documented. Higher verbal and nonverbal functioning were associated with greater improvement. CONCLUSIONS: Findings are suggestive of the potential effectiveness of social-skills training in groups for children with brain tumors. Multisite, randomized, controlled studies are recommended as the next step.