These disorders, although rare, should be considered in the approach to a child with dysmorphism, developmental delay, skeletal deformities, and visceromegaly.”
“Schizophrenia remains among the most prevalent neuropsychiatric disorders, and current treatment options are accompanied by unwanted side effects. New treatments that better address
core features of the disease with minimal side effects are needed. As a new therapeutic approach, 1-(4-fluoro-phenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) is currently in human clinical trials for the treatment of schizophrenia. Here, we characterize the preclinical functional activity of ITI-007. ITI-007 is a potent 5-HT2A receptor ligand (K (i) STI571 = 0.5 nM) with strong affinity for dopamine (DA) D-2 receptors (K (i) = 32 nM) and the serotonin transporter (SERT) (K (i) = 62 nM) but negligible binding to receptors
(e.g., H-1 histaminergic, Pitavastatin molecular weight 5-HT2C, and muscarinic) associated with cognitive and metabolic side effects of antipsychotic drugs. In vivo it is a 5-HT2A antagonist, blocking (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced headtwitch in mice with an inhibitory dose 50 (ID50) = 0.09 mg/kg, per oral (p.o.), and has dual properties at D-2 receptors, acting as a postsynaptic D-2 receptor antagonist to block D-amphetamine hydrochloride (D-AMPH) hyperlocomotion (ID50 = 0.95 mg/kg, p.o.), yet acting as a partial agonist at presynaptic striatal D2 receptors in assays measuring striatal DA neurotransmission. Further, in microdialysis studies, this compound significantly and preferentially enhances
mesocortical DA release. At doses relevant for antipsychotic activity in rodents, ITI-007 has no demonstrable cataleptogenic activity. ITI-007 indirectly modulates glutamatergic neurotransmission by increasing phosphorylation of GluN2B-type N-methyl-d-aspartate (NMDA) receptors and preferentially increases phosphorylation of glycogen synthase kinase 3 beta (GSK-3 beta) in mesolimbic/mesocortical dopamine systems. The combination of in vitro and in vivo activities of this compound support its development for the treatment CUDC-907 of schizophrenia and other psychiatric and neurologic disorders.”
“The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors.