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The permeability characteristics of 33 amphoteric drugs (about 64% zwitterions at physiological pH) were studied using the parallel artificial membrane permeability assay (PAMPA) at pH 6.5. The PAMPA data were modified to include the paracellular permeability component found in cellular monolayers based on a newly generalized version of a popular model devised for Caco-2 cells. These “in combo” PAMPA data were used to predict the human absolute bioavailability of the ampholytes. The analysis produced a good fit, with only five outliers whose transport properties, could be rationalized by (a) nonpassive permeability processes, (b) metabolic instability, and (c) the possible sensitivity to microclimate pH effects in the case of acidic ampholytes. With the exception of two compounds, all of the ampholytes with bioavailability <50% were predominantly transported by the paracellular route, surprisingly with several of the compounds having molecular weights exceeding 350 Da. [ABSTRACT FROM AUTHOR]

An in situanalytical approach to the measurement of supported liquid membrane permeability is reported. The method consists of a spectrophotometric method to measure transport through a membrane-supported lipid solution, using a rotating-diffusion cell configuration to overcome limits arising from transport through the aqueous solution boundary layer in stationary systems. Rotation frequencies are almost two orders of magnitude higher than those employed previously for rotating-diffusion studies of membrane transport. The method is illustrated with the transport of warfarin [1-(4′-hydroxy-3′-coumarinyl)-1-phenyl-3-butanone]. The use of the rotating-diffusion approach permits accurate calculation of the aqueous phase boundary layer thickness, which has hitherto been treated as an adjustable parameter in studies of membrane permeability. Further, it is shown that the analyte diffusion coefficient can be determined readily using liquid–liquid electrochemistry. [ABSTRACT FROM AUTHOR]

The purpose of this study is to investigate whether listening to music and white noise affects functional connectivity on scalp electroencephalography (EEG) in neonates in the neonatal intensive care unit. Nine neonates of ≥34 weeks' gestational age, who were already undergoing clinical continuous EEG monitoring in the neonatal intensive care unit, listened to lullaby-like music and white noise for 1 hour each separated by a 2-hour interval of no intervention. EEG segments during periods of music, white noise, and no intervention were band-pass filtered as delta (0.5-4 Hz), theta (4-8 Hz), lower alpha (8-10 Hz), upper alpha (10-13 Hz), beta (13-30 Hz), and gamma (30-45 Hz). Synchronization likelihood was used as a measure of connectivity between any 2 electrodes. In theta, lower alpha, and upper alpha frequency bands, the synchronization likelihood values yielded statistical significance with sound (music, white noise and no intervention) and with edge (between any 2 electrodes) factors. In theta, lower alpha, and upper alpha frequency bands, statistical significance was obtained between music and white noise (t = 3.12, 3.32, and 3.68, respectively; P <.017), and between white noise and no intervention (t = 4.51, 3.09, and 2.95, respectively, P <.017). However, there was no difference between music and no intervention. Although limited by a small sample size and the 1-time only auditory intervention, these preliminary results demonstrate the feasibility of EEG connectivity analyses even at bedside in neonates on continuous EEG monitoring in the neonatal intensive care unit. They also point to the possibility of detecting significant changes in functional connectivity related to the theta and alpha bands using auditory interventions. [ABSTRACT FROM AUTHOR]

We report on a woman with first-episode schizophrenia with grandiose delusions. She developed a bizarre delusion that she was 'Jesus', who had special powers to talk to animals and predict the future. The grandiose delusions were maintained by her positive emotions, positive imagery of becoming an extraordinary person, and cognitive biases. With the application of cognitive and affective model for formulation of an intervention plan, it was found that the patient had improvement in lowered shamefulness about herself and skills of setting appropriate expectations. The assessment and treatment process of this patient shows the value of applying theory to case formulation and making a care plan for the case management service for patients with first-episode psychosis. This report has clear limitations in that it is a discussion of a single patient, and the case formulation is speculative at this time. The formation and maintenance of grandiose delusions are discussed from the cognitive and affective perspectives. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented on a case of a 33 year-old Chinese woman with astroblastoma located close to the left cortical surface of the brain.

Tumor progression loci-2 (Tpl2) (Cot/MAP3K8) is a serine/threonine kinase in the MAP3K family directly upstream of MEK. Recent studies using Tpl2 knockout mice have indicated an important role for Tpl2 in the lipopolysaccharide (LPS) induced production of tumor necrosis factor (TNF-) and other proinflammatory cytokines involved in diseases such as rheumatoid arthritis. Initial 4-anilino-6-aminoquinoline-3-carbonitrile leads showed poor selectivity for Tpl2 over epidermal growth factor receptor (EGFR) kinase. Using molecular modeling and crystallographic data of the EGFR kinase domain with and without an EGFR kinase-specific 4-anilinoquinazoline inhibitor (erlotinib, Tarceva), we hypothesized that we could diminish the inhibition of EGFR kinase by substitution at the C-8 position of our 4-anilino-6-aminoquinoline-3-carbonitrile leads. The 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles were prepared from the appropriate 2-substituted 4-nitroanilines. Modifications to the C-6 and C-8 positions led to the identification of compounds with increased inhibition of TNF- release from LPS-stimulated rat and human blood, and these analogues were also highly selective for Tpl2 kinase over EGFR kinase. Further structure−activity based modifications led to the identification of 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-(1-methyl-1H-imidazol-4-yl)methylaminoquinoline-3-carbonitrile, which demonstrated in vitro as well as in vivo efficacy in inhibition of LPS-induced TNF- production. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin receptor pathways and thus an attractive therapeutic target for diabetes and obesity. Starting with a high micromolar lead compound, structure-based optimization of novel PTP1B inhibitors by extension of the molecule from the enzyme active site into the second phosphotyrosine binding site is described. Medicinal chemistry, guided by X-ray complex structure and molecular modeling, has yielded low nanomolar PTP1B inhibitors in an efficient manner. Compounds from this chemical series were found to be actively transported into hepatocytes. This active uptake into target tissues could be one of the possible avenues to overcome the poor membrane permeability of PTP1B inhibitors. [ABSTRACT FROM AUTHOR]

The successful synthesis of terminal lead aryloxides is shown to be dependent upon reaction conditions, including choice of solvent and alkali metal aryloxide precursor. [ABSTRACT FROM AUTHOR]