Maintenance therapy with once-monthly administration of long-acting injectable risperidone in patients with schizophrenia or schizoaffective disorder: a pilot study of an extended dosing interval

BACKGROUND: Several clinical studies have established the efficacy, safety, and tolerability of long-acting risperidone administered once every 2 weeks in patients with schizophrenia or schizoaffective disorder. This report evaluates preliminary efficacy, safety, tolerability, and pharmacokinetic data for a novel (once-monthly) administration of long-acting injectable risperidone 50 mg in patients with schizophrenia or schizoaffective disorder. METHODS: Clinically stable patients participated in a 1-year, open-label, single-arm, multicenter pilot study. During the 4-week lead-in phase, patients received long-acting risperidone 50 mg injections every 2 weeks, with 2 weeks of oral risperidone supplementation. Injections of long-acting risperidone 50 mg every 4 weeks followed for up to 48 weeks, without oral supplementation. The primary endpoint was relapse; other assessments included PANSS, CGI-S, adverse event reports, and determination of risperidone and 9-hydroxyrisperidone plasma concentrations. RESULTS: Twelve patients in the intent-to-treat population (n = 67) met relapse criteria (17.9%). Relapse risk at 1 year was estimated as 22.4%. Non-statistically significant improvements in symptoms (PANSS) and clinical status (CGI-S) at endpoint were observed. The most common adverse events included schizophrenia aggravated not otherwise specified (19.5%), anxiety (16.1%), insomnia (16.1%), and headache (11.5%). There were no unexpected safety and tolerability findings. Mean plasma concentrations for risperidone and 9-hydroxyrisperidone were generally stable during the study. CONCLUSION: Once-monthly dosing of long-acting risperidone was well tolerated, associated with a relatively low relapse rate (similar to that reported with other antipsychotics), and maintained the clinically stable baseline status of most patients. Although the results suggest that some symptomatically stable patients with schizophrenia or schizoaffective disorder might be safely managed with long-acting risperidone 50 mg once monthly, these findings alone do not identify which patients will have a sufficient therapeutic benefit nor do they quantify comparative effects of standard and altered dosing. Study limitations (the open-label pilot study design, small sample size, and lack of a concurrent biweekly treatment arm) prevent broad interpretations and extrapolations of results. Controlled studies would be required to support a recommendation for alternative dosing regimens

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Composing Well-Defined Stimulus-Responsive Materials Through Postpolymerization Modification Reactions

Postpolymerization modification—the installation of functional groups into a premade, reactive polymeric precursor—is emerging as an advantageous synthetic strategy toward tailored materials. In this article, the preparation of environmentally sensitive, “smart,” polymers by virtue of postpolymerization modification is presented. The underlying fundamentals of different types of stimulus-responsiveness are highlighted with an emphasis on thermo­responsiveness, encompassing lower and upper critical solution temperature (LCST and UCST) behavior. Using a range of postpolymerization modifications as examples, properties imparted through incorporation of specific functional groups and their structure–property relations are discussed. Strategies for an appropriate choice of functionality in order to obtain well-defined materials with custom-made behavior are presented